Heterocyclic ether compounds useful in controlling neurotransmitter release

ABSTRACT

Novel heterocyclic ether compounds of the formula: ##STR1## wherein *, A,B, n, R 1 , R 2  and X are specifically defined, or pharmaceutically-acceptable salts or prodrugs thereof, which are useful in selectively activating or inhibiting neurotransmitter release; to therapeutically-effective pharmaceutical compositions of these compounds; and to the use of said compositions to activate or inhibit neurotransmitter release in mammals.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. Ser. No. 08/391,749filed on Feb. 21, 1995, now abandoned, which is a continuation-in-partof U.S. Ser. No. 08/129,223 filed on Oct. 4, 1993, now abandoned, whichis a continuation-in-part of Ser. No. 08/126,491 filed Sep. 28, 1993abandoned which is a continuation-in-part of U.S. Ser. No. 07/959,005filed on Oct. 9, 1992, now abandoned.

TECHNICAL FIELD

This invention relates to heterocyclic ether compounds which selectivelycontrol neurotransmitter release; to therapeutically-effectivepharmaceutical compositions of these compounds; and to the use of saidcompositions to selectively control neurotransmitter release in mammals.

BACKGROUND OF THE INVENTION

Dopamine is widely recognized as an important neurotransmitter in thecentral nervous systems in humans and animals, and itself possessesintrinsic pharmalogical properties. Many aspects of the pharmacology ofdopamine have been reviewed by Roth and Elsworth (BiochemicalPharmacology of Midbrain Dopamine Neurons. In: Psychopharmacology: Thefourth generation of progress, F. E. Bloom and D. J. Kupfer, Eds., RavenPress, NY, 1995, pp 227-243). One group of compound studied extensivelyis that of pharmacologic agents that modify dopamine release or therelease of other neurotransmitters.

Control of dopamine or neurotransmitter release is an important utilityin-and-of itself. Studies of dopamine and neurotransmitter release haveled to the discovery of important pharmacologically active compounds.However, new and selective neurotransmitter controlling agents are stillbeing sought, in the hope that one or more will be useful in as yetpoorly controlled disease states or behavior models.

For example, dementia, such as is seen with Alzheimer's disease orParkinsonism, remains largely untreatable. Symptoms of chronicalcoholism and nicotine withdrawal involve aspects of the centralnervous system, as does the behavioral disorder Attention-DeficitDisorder (ADD). Specific agents for treatment of these and relateddisorders are few in number or non-existent.

One means of studying neurotransmitter release is to study theactivation of cholinergic channel mediated release (Wonanacott et al.,Presynaptic nicotinic autoreceptors and heteroreceptors in the CNS. In:Effects of Nicotine on Biological Systems II: Advances inPharmacological Sciences. P. B. S. Clark et al, Eds., Birkhauser, Basel,1995, pp. 87-94) . The biological effects of acetylcholine, for example,are mediated by distinct specific interactions with different subtypesof cholinergic receptors. The two distinct subfamilies of cholinergicreceptors are defined as nicotinic cholinergic receptors and muscariniccholinergic receptors. (See Taylor, Goodman and Gilman's ThePharmacological Basis of Therapeutics, 8th ed.) The responses of thesereceptor families are mediated by two entirely different classes ofsecond messenger systems. Nicotinic receptor-activation mediates theconductance of specific extracellular ions (e.g. Na⁺, K⁺ and Ca⁺⁺)through the neuronal membrane, whereas muscarinic receptors are coupledto intracellular systems that contain complex molecules such asG-proteins and inositol phosphates. Thus, the biological consequences ofnicotinic cholinergic channel activation by acetylcholine are distinctfrom those of muscarinic activation. In an analogous manner, inhibitionof nicotinic cholinergic channels result in still other effects distinctand different from those arising from muscarinic receptor inhibition.

In fact, there is reason to expect or suggest that agents that controlneurotramnsmitter release and which bind at the nicotinic cholinergicreceptors may show activity in addressing some untreatable disorders ofthe central nervous system, including those mentioned above. Partialevidence in support of this suggestion is set forth briefly below.

The precise molecular lesions that contribute to the morphological andfunctional deficits associated with dementia are not fully understood,despite intensive research efforts. However, the most consistentabnormality for Alzheimer's disease, as well as for vascular dementiaand cognitive impairment due to organic brain disease related toalcoholism, is the degeneration of the cholinergic system arising fromthe basal forebrain (BF) to both the cortex and hippocampus (Bigl etal., in Brain Cholinergic Systems, M. Steriade and D. Biesold, eds.,Oxford University Press, Oxford, 1990, pp. 364-386). In particular,neurochemical evidence from the brains of patients afflicted withAlzheimer's disease has revealed reliable decreases in markers ofcholinergic neuronal function (Perry et al., Br. Med. J.,2:1457, 1978;Reisine et al., Brain Res., 159:477, 1978; Coyle et al., Science,219:1184,1 983; and McGeer et al., Neurology, 34:741, 1984). While thereare a number of other neurotransmitter systems affected by Alzheimer'sdisease (Davies, Med. Res. Rev., 3:221, 1983), the relative occurrenceof such abnormalities is less consistent or the effect is less profoundthan the decreases in these cholinergic neuronal function markers. Morespecifically, substantial reductions (30-50%) in nicotinic cholinergicchannel receptors have been consistently reported in the brains ofpatients with Alzheimer's disease or Parkinson's disease (Kellar et al.,Brain Res., 436:62,1987; and Whitehouse et al., Neurol., 38:720,1988),whereas changes in muscarinic cholinergic receptors are less remarkableand more dependent on receptor subtype.

However, degeneration of the cholinergic neurotransmitter system hasalso been reported in aged, but otherwise healthy, individuals (for areview, see Giacobini, J. Neurosci. Res., 27:548, 1990). Moreover, agingmay cause a decrease in the cholinergic impulses flow from the basalforebrain to the cortex (Aston-Jones et al., Brain Res., 325:271, 1985).Consistent with these findings are pharmacological studies suggestingthat cholinergic mechanisms are, at least in part, responsible for thememory disturbances in aged animals and humans not suffering fromAlzheimer's disease (Drachman and Leavitt, Arch. Neurol., 30:113, 1974;Bartus et al., Science, 217:408, 1982).

Other clinical signs associated with the neurodegenerative process ofAlzheimer's disease include decreases in regional cerebral blood flowand cerebral glucose utilization, in regions which largely parallel theareas where cholinergic deficits occur (Ingvar and Risberg, Exp. BrainRes., 3:195, 1962; Ingvar et al., Aging: Alzheimer's Disease. SenileDementia and Related Disorders. Vol. 7, R. Katzman, R. D. Terry, and K.L. Bick, eds., Raven Press, 1978, p: 203; and Dastur, J. Cerebral BloodFlow & Metabol., 5:1, 1985). Recent clinical evidence suggests that thisabnormality observed in Alzheimers disease patients reflects regionalnicotinic cholinergic deficits (Prohovnik, Neurobiol. Aging, 11:262,1990). In agreement with this finding, is the discovery that regulationof cerebral blood flow in the frontoparietal cortex in the rat, governedby the basal forebrain, is also dependent upon nicotinic mechanisms(Arneric, J. Cerebral Blood Flow & Metabol., 9 (Suppl. 1): S502, 1989).

Pilot clinical studies suggest that nicotine may be useful for the acutetreatment of deficits in attention and information processing associatedwith Alzheimer's disease (Sahakian et al., Brit. J. Psych., 154:797,1989; Newhouse et al., Psychopharmacol., 95:171, 1988). It has beenshown that both acutely- and chronically-administered nicotine enhancescognitive function in rats (Levin et al., Behav. Neural Biol., 53:269,1990), an effect that is also observed in aged animals (Cregan et al.,Soc. Neurosci. Abstract, 15: 2952, 1989). Nicotine is expected to beneuroprotective, because it has been shown that nicotine can preventpre-synaptic loss of functional dopaminergic neurons in animal studieswith induced brain injuries (Janson et al., Prog. Brain Res., 79:257,1989; and Owman et al., Prog. Brain Res., 79:267, 1989).

Other situations where beneficial therapeutic outcome may be achieved orimproved through administration of nicotine or a cholinergic channelactivator, because of neurotransmitter releasing and anxiolyticproperties of these agents, include attention-deficit disorder and drugwithdrawal.

Attention-deficit disorder (ADD), with or without hyperactivity, is abehavioral disorder characterized by distractibility and impulsiveness.Children with this disorder are handicapped by their inability toconcentrate and control their impulsivity, especially in settingsrequiring sustained attention, for example, in school. Neurochemically,ADD is thought to be the result of a decreased release of dopamine(Oades, R. D., Prog. Neurobiol., 29:365391, 1987; Rogeness et al., J.Am. Acad. Child Adolescent Psychiatry, 31:765-781, 1992; Shenker, A.,Adv. Pediatr., 39:337-382, 1992). Dopaminergic stimulation has beenshown to be important in further regulating the release of acetylcholinefrom areas of the brain involved with attentional precessing such as thecerebral cortex and hippocampus (Day, J. and Fibiger, H. C., Synapse,12:281-286, 1992). Nicotine, d-amphetamine and methylphenidate eachenhance the release of dopamine and acetylcholine (Day, J. and Fibiger,H. C., Neuroscience, 54:643-648, 1993), although by differentpharmacological mechanisms (Lefkowitz, R. J., Hoffman, B. B., andTaylor, P., Neurohumoral transmission: The autonomic and somatic motornervous systems. In: Goodman and Gilman's, The Pharmacological Basis ofTherapeutics, (eds. A. G. Gilman, T. W. Rall, A. S. Nies, P. Taylor)Pergamon Press, New York, 1990, pp. 244-268.). While a cure for thisdisorder has not been found, stimulants, such as d-amphetamine andmethylphenidate which enhance the release of dopamine and acetylcholine,have been used successfully in management of the behavioralmanifestations of ADD. Nicotine, because of its ability to improveconcentration and task performance (F. T. Etscom, U.S. Pat. No.4,597,961, issued Jul. 1, 1986; and D. M. Warburton and K. Wesnes inSmoking Behavior, R. E. Thornton, ed., Churchill-Livingston, Edinburgh,1978, pp. 19-43) is also potentially useful in treating ADD. Pilotclinical studies using transdermal patches containing nicotine recentlyhave been shown to improve the symptoms of ADD (Levine et al., Soc. forResearch on Nicotine and Tobacco, March 24-25, P63, 1995). Thus,enhancing the release of dopamine and acetylcholine with other compoundsthat activate nicotinic cholinergic channels may also have clinicalutility in treating the symptoms of ADD, especially, if those compoundshave a safer side effect profile compared to nicotine.

Schizophrenia is considered to be the result of overactive dopaminerelease (Kahn, R. S. and David, K. L., New Developments in dopamine andschizophrenia. In: Psychopharmacology: The fourth generation ofprogress, op. cit). Thus compounds that inhibit dopamine might be usefulin the treatment of this condition. Evidence for the potential benefitsof nicotinic cholinergic channel receptor-based therapies inschizophrenia come from the observation that certain nicotinic channelligands have been shown to be neuroprotective (e.g.;, Freedman et al.,In: Effects of Nicotine on Biological Systems II, Advances inPharmacological Sciences, op. cit., pp.307-312; Martin et al., Drug Dev.Res., 31:135-141, 1994;Akaike et al., Brain Res 644:181-187, 1994; Marinet al., Neuroreport, 5:1977-1980, 1994). Epidemiologic data indicatingincreased prevalence of smoking among patients with schizophrenia(>80%), may be an attempt to self-medicate both for palliative andneuroprotective benefits. Moreover, given the cognition-enhancingpotential of nicotinic channel modulators, and the ability of(-)-nicotine to normalize sensory-gating impairments, it is possiblethat such compounds may be useful in treating two major dysfunctionalmanifestations of schizophrenia.

Parkinsonism is a clinical syndrome with four cardinal features:bradylinesia, muscular rigidity, resting tremor, and abnormalities ofposture and gait. Classical investigations have clearly established thatthe basal ganglia and the nigrostriatal dopamine system as the site ofthe fundamental neurochemical lesion of the disease (Korczyn, A. D.,Parkinson's Disease. In: Psychopharmacology: The Fourth Generation ofProgress. op. cit., pp. 1479-1484.). Clinical studies have demonstratedthe efficacy of restoring dopamine release, or mimic dopamine receptoractivation. The therapeutic effects of nicotine in Parkinson's diseasewere described more than half a century ago (Moll, Brit. Med. J. 1:1079, 1926), and interest has been renewed more recently (Janson et al,In: Effects of Nicotine on Biological Systems II, Advances inPharmacological Sciences, op. cit., pp. 321-328). In addition, nicotinehas been employed as a potential drug in the treatment of anothermovement disorder, Tourette's disease (McConville et al., Am. J.Psychiatry, 148:739, 1991; Silver et al, In: Effects of Nicotine onBiological Systems II, Advances in Pharmacological Sciences, op. cit.,pp. 293-299.). Development of compounds that provide a more selectiveand persistent depolarization of cholinergic channel receptors in thebrain than nicotine may provide a safer and more effective treatment ofParkinson's disease and related movement disorders.

The nicotine withdrawal syndrome associated with smoking cessation ischaracterized by craving for nicotine, irritability, frustration oranger, anxiety, difficulty concentrating, restlessness, decreased heartrate and increased appetite and weight gain. Nicotine has, notsurprisingly, been found to ease the withdrawal experienced by thoseattempting to break tobacco dependencies. As early as 1942, Johnstonreported (L. Johnston, Lancet, 2:742, 1942) that injections of nicotinerelieved the withdrawal symptoms experienced by cigarette smokers whenthey stopped smoking. More recently, in double-blind studies, nicotinewas far superior to a placebo in suppressing or preventing theappearance of many of the signs and symptoms of withdrawal (J. R. Hugheset al., Psychopharmacology, 83:82-7, 1984; N. G. Schneider et al.,Addictive Behavior, 9:149-56, 1984; R. J. West et al., Journal ofAddiction, 79:215-9, 1984; K. O. Fagerstrom in Nicotine Replacement: aCritical Evaluation, O. F. Pomperleau and C. S. Pomperleau, eds., AlanR. Liss, Inc., New York, 1988, pp. 109-28; and J. E. Henningfield and D.R. Jasinski, ibid, pp.3561). Irritability and impatience were shown tohave been reduced in at least five independent controlled studies, whileanxiety and difficulty concentrating were shown to have been reduced inat least two studies. One approach to alleviating the symptoms oftobacco withdrawal has been to develop more efficient methods ofdelivering nicotine, itself, for example, in transdermal patches (F. T.Etscorn, U.S. Pat. No. 4,597,961, issued Jul. 1, 1986). The majorproblem with this approach is the non-selective effect of nicotine andin particular, the stimulant effects of increasing cardiac workload andoxygen demand that nicotine has on the heart. A selective cholinergicchannel activator would be expected to be equally efficacious inrelieving withdrawal symptoms with fewer cardiovascular liabilities.

Existing cholinergic channel agonists are therapeutically suboptimal intreating the conditions discussed above. For example, such compoundshave unfavorable pharmacokinetics (e.g., arecoline and nicotine), poorpotency and lack of selectivity (e.g., (-)-nicotine), poor CNSpenetration (e.g., carbachol) or poor oral bioavailability (e.g.,nicotine). In addition, other agents have many unwanted central agonistactions, including hypothermia, hypolocomotion and tremor and peripheralside effects, including miosis, lachlymation, defecation and tachycardia(Benowitz et al., in: Nicotine Psychopharmacology, S. Wonnacott, M. A.H. Russell, & I. P. Stolerman, eds., Oxford University Press, Oxford,1990, pp. 112-157; and M. Davidson, et al., in Current Research inAlzheimer Therapy, E. Giacobini and R. Becker, ed.; Taylor & Francis:New York, 1988; pp 333-336).

Various heterocyclic 2-pyrrolidinyloxy-substituted compounds withanalgesic and hypotensive activities have been disclosed by Scheffler etal. (U.S. Pat. No. 4,643,995) and Tomioka et al. (Chem. Pharm. Bull,38:2133-5, 1990).

Certain other 2-pyridyloxy-substituted compounds are disclosed interalia by Engel et al. in U.S. Pat. No. 4,946,836 as having analgesicactivity.

Various other compounds having a pyrrolidine or azetidine moietysubstituted at the 3-position with a heterocycloxy group have also beendisclosed (cf U.S. Pat. No. 4,592,866 to A. D. Cale; U.S. Pat. No.4,705,853 to A. D. Cale; U.S. Pat. No. 4,956,359 to Taylor et al.; andU.S. Pat. No. 5,037,841 to Schoehe et al. and European patentapplication EP296560A2, to Sugimoto et al.).

SUMMARY OF THE INVENTION

In accordance with the present invention, it has been found that certain3-pyridyloxymethyl heterocyclic ether compounds are selective and potentcholinergic compounds useful in controlling neurotransmitter release.

In its principle aspect, the present invention provides a class ofheterocyclic ether compounds of formula (I) ##STR2## or apharmaceutically acceptable salt thereof, wherein * indicates a chiralcenter and n is 1, 2, or 3. The substituent group R¹ is selected from H,allyl, or C₁ -C₆ -alkyl; R² is a hydrogen or a single chiral or achiralsubstituent, and when substituted at the 3-position is a C₁ -C₃ -alkylgroup; or when substituted at the 4position is selected from the groupconsisting of: CH₂ OH, CH₂ F, CH₂ -O-methyl, Br, Cl, F, OH, CN, C₁ -C₃-alkoxyl, as defined below, O-CO-CH₃ and O-methanesulfonyl; or whensubstituted at the 5position is a C₁ -C₃ -alkyl group.

The group A is selected from the group consisting of ##STR3## wherein R³is H or C₁ -C₆ -alkyl.

The group D is selected from the group consisting of: ##STR4## whereiny=1, 2 or 3; and R⁴, when substituted at the 2-position, is selectedfrom hydroxy, C₁ -C₃ -alkyl, C₁ -C₃ -alkoxy, F, or Cl; or R⁴, whensubstituted at the 4, 5 or 6-position is selected from the the groupconsisting of (a) hydroxyl, CF₃, C₁ -C3-alkoxy, nitro, amino, N(C₁ -C₃-alkyl)-COCl-C₃ -alkyl, C₁ -C₃ -alkylamino, as defined below, di(C₁ -C₃-alkyl)amino, as defined below, cyano, CO-OH, CO-O-C₁ -C₃ -alkyl,CO-NH₂, CO-NH-C₁ -C₃ -alkyl, CO-N-(C₁ -C₃ -alkyl)₂, or CO-NH-benzyl; or(b) F, Cl, Br or C₁ -C₃ -alkyl; and with the requirements that when y is1 or 2, then one R⁴ group must be substituted at the 4-, 5- or6-position and be selected from group (a) above, and when y is 3 then atleast two of the substituents must be selected from group (b) above;##STR5## X is --O-- or --S--, preferrably --O--; with the requirementthat when A is ethylene the chiral center must be (S); or apharmaceutically-acceptable salt or prodrug thereof.

Another aspect of the invention comprises therapeutically-effectivepharmaceutical compositions containing these compounds.

Still another aspect of this invention comprises the use of saidcompositions to selectively control neurotransmitter release in mammals.

DETAILED DESCRIPTION OF THE INVENTION

In one preferred embodiment of the instant invention are compounds offormula (1) or their pharmaceutically-acceptable salts or prodrugs,wherein the chiral center is of the (S) configuration.

In another preferred embodiment of the instant invention are compoundsof formula (I) or their pharmaceutically-acceptable salts or prodrugs,wherein the chiral center is of the (R) configuration.

More preferred embodiments of the present invention are represented bycompounds of formula (I), wherein n is 1 or 2, R¹ is H or methyl, R² isas defined above, R³ is H, and D is ##STR6## wherein R⁴ and y are asdefined above; or a pharmaceutically-acceptable salt or prodrug thereof.

Additional preferred embodiments of the present invention arerepresented by compounds of formula (I), wherein:

n is 1, R¹ is H or methyl, and R² and R³ are H; or

n is 2, R¹, R² and R³ are H, or the compound is of the (S)-configurationand R¹ is methyl and R² and R³ are H; and

D is: ##STR7## wherein R⁴ and y are as defined above; or apharmaceutically-acceptable salt or prodrug thereof.

The following are representative of the novel compounds of the presentinvention:

2-((1-methyl-2-(S)-pyrrolidinyl)methoxy)pyrazine;

2-((1-methyl-2-(R)-pyrrolidinyl)methoxy)-6-chloropyridazine;

3-(1-(1-methyl-2-(S)-pyrrolidinyl)ethoxy)pyridine;

2-(2-(S)-azetidinylmethoxy)pyrazine;

2-((1-methyl-2-(S)-azetidinyl)methoxy)pyrazine;

2-((1-methyl-2-(S)-pyrrolidinyl)methoxy)thiazole;

3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)-6-chloropyridazine;

6chloro-3-((1-methyl-2-(S)-azetidinyl)methoxy)pyridazine;

3-((cis-1,5-dimethyl-2-(S)-pyrrolidinyl)methoxy)pyridine;

3-((trans-1-methyl-4-hydroxy-2(S)-pyrrolidinyl)methoxy)pyridine;

3-((trans-1,4dimethyl-2-(S)-pyrrolidinyl)methoxy)pyridine;

3-((trans-1-methylethyl-2-(S)-pyrrolidinyl)methoxy)pyridine;

3-(1-methyl-2-(S)-pyrrolidinylmethoxy)-5-trifluoromethylpyridine;

3-((trans-4-methoxy-1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine;

3-((cis-4-hydroxymethyl-1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine;

3-((4-methoxymethyl-1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine;

3-((trans-4-cyanomethyl-1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine;

3-((1-methyl-2-(R)-pyrrolidinyl)methoxy)-5-trifluoromethylpyridine;

3-((cis-1-methyl-3-propyl-2-pyrrolidinyl)methoxy)pyridine;

3-((cis-3-propyl-2-pyrrolidinyl)methoxy)pyridine;

3-(2-(S)-pyrrolidinylmethoxy)-5-trifluoromethylpyridine;

3-(2-(R)-pyrrolidinylmethoxy)-5-trifluoromethylpyridine;

3-(2-S)-azetidinylmethoxy)-5-trifluoromethylpyridine;

3-((trans-4-hydroxy-2-(S)-pyrrolidinyl)methoxy)pyridine;

3-((trans-4-methoxy-2-(S)-pyrrolidinyl)methoxy)pyridine;

3-((cis-4-fluoro-1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine;

3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridazine;

3-((trans4-hydroxymethyl-1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine;

(1-methyl-2-(S)-pyrrolidinylmethoxy)pyrimidine;

3-(2-(S)-azetidinylmethoxy)-6-chloropyridazine;

3-((trans-4-methanesulfonyloxy-1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine;

6-hydroxymethyl-3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine;

3-(trans-1,5-dimethyl-2-(S)-pyrrolidinyl)methoxy)pyridine;

3-((cis-4-cyano-1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine;

3-((cis-5-n-butyl-1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine;

3-((cis-fluoromethyl-1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine;

3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)-5-nitro-pyridine;

3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)-5-aminopyridine;

3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)-5-methylamino-pyridine;

3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)-5-methylamino-pyridine;

3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)-5-acetylamino-pyridine;

3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)-5-methoxy-pyridine;

3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)-5-cyano-pyridine;

3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine-5-carboxylic acidmethyl ester;

3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine-5-carboxylic acid;

3-(2-(2-(S)-pyrrolidinyl)ethoxy)pyridine;

3-(2-(1-methyl-2-(S)-pyrrolidinyl)ethoxy)pyridine;

3-(2-(2-(S)-pyrrolidinyl)ethoxy)-6-chloropyridine;

3-(2-(1-methyl-2-(S)-pyrrolidinyl)ethoxy)-6-chloropyridine;

3-(2-(S)-pyrrolidinylmethylthioxy)-6-chloropyridine; and

3-(1-methyl-2-(S)-pyrrolidinylmethylthioxy)-6-chloropyridine;

or a pharmaceutically-acceptable salt or prodrug thereof.

The following are representative of the preferred compounds of thepresent invention:

3-(1-(1-methyl-2-(S)-pyrrolidinyl)ethoxy)pyridine;

2-(2-(S)-azetidinylmethoxy)pyrazine;

2-((1-methyl-2-(S)-azetidinyl)methoxy)pyrazine;

3-((trans-1,4-dimethyl-2-(S)-pyrrolidinyl)methoxy)pyridine;

3-(trans-1-methyl-4-ethyl-2-(S)-pyrrolidinyl)methoxy)pyridine;

3-(1-methyl-2-(S)-pyrrolidinylmethoxy)-5-trifluoromethylpyridine;

3-((transcyanomethyl-1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine;

3-((1-allyl-2-(S)-pyrrolidinyl)methoxy)-5-bromopyridine;

3-((cis-3-propyl-2-pyrrolidinyl)methoxy)pyridine;

3-(2-(S)-pyrrolidinylmethoxy)-5-trifluoromethylpyridine;

3-(2-(R)-pyrrolidinylmethoxy)-5-trifluorimethylpyridine;

3-(2-(S)-azetidinylmethoxy)-5-trifluoromethylpyridine;

3-((cis-4-fluoro-1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine;

5(1-methyl-2-(S)-pyrrolidinylmethoxy)pyrimidine;

3-(2-(S)-azetidinylmethoxy)-6-chloropyridazine;

5amino-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine; and

5nitro-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine;

or a pharmaceutically-acceptable salt or prodrug thereof.

The following are representative of the more preferred novel compoundsof the present invention:

2-(2-(S)-azetidinylmethoxy)pyrazine;

3-(1-methyl-2-(S)-pyrrolidinylmethoxy)-5-trifluoromethylpyridine;

3-(2-(R)-pyrrolidinylmethoxy)-5-trifluoromethylpyridine;

3-(2-(S)-azetidinylmethoxy)-5-trifluoromethylpyridine;

5-amino-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine, and

5-nitro-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine;

or a pharmaceutically-acceptable salt or prodrug thereof.

In another embodiment of the instant invention are compounds of formula(I) or their pharmaceutically-acceptable salts or prodrugs, wherein thechiral center is of the (S) configuration.

Representative of the compounds of the invention wherein the chiralcenter is of the (S) configuration are:

2-((1-methyl-2-(S)-pyrrolidinyl)methoxy)pyrazine;

3-(1-(1-methyl-2-(S)-pyrrolidinyl)ethoxy)pyridine;

2-(2-(S)-azetidinylmethoxy)pyrazine;

2-((1-methyl-2-(S)azetidinyl)methoxy)pyrazine;

2-((1-methyl-2-(S)-pyrrolidinyl)methoxy)thiazole;

3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)-6-chloropyridazine;

6chloro-3-((1-methyl-2-(S)-azetidinyl)methoxy)pyridazine;

3-((cis-1,5-dimethyl-2-(S)-pyrrolidinyl)methoxy)pyridine;

3-((trans-1-methyl-4-hydroxy-2-(S)-pyrrolidinyl)methoxy)pyridine;

3-((trans-1,4-dimethyl-2-(S)-pyrrolidinyl)methoxy)pyridine;

3-((trans-1-methyl-4-ethyl-2(S)-pyrrolidinyl)methoxy)pyridine;

3-(1-methyl-2-(S)-pyrrolidinylmethoxy)-5-trifluoromethylpyridine;

3-((trans-4-methoxy-1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine;

3-((cis-4-hydroxymethyl-1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine;

3-((4-methoxymethyl-1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine;

3-((trans-4-cyanomethyl-1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine;

3-((1-allyl-2-(S)-pyrrolidinyl)methoxy)-5-bromopyridine;

3-(2-(S)-pyrrolidinylmethoxy)-5-trifluoromethylpyridine;

3-(2-(S)-azetidinylmethoxy)-5-trifluoromethylpyridine;

3-((trans-4-hydroxy-2-(S)-pyrrolidinyl)methoxy)pyridine;

3-((trans-4methoxy-2-(S)-pyrrolidinyl)methoxy)pyridine;

3-(cis4-fluoro-1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine;

3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridazine;

3-((1-allyl-2-(S)-pyrrolidinyl)methoxy)pyridine;

3-((trans-4-hydroxymethyl-1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine;

5(1-methyl-2-(S)-pyrrolidinylmethoxy)pyrimidine;

3-(2-(S)-azetidinylmethoxy)-6-chloropyridazine;

3-((trans-4-methanesulfonyloxy-1-methyl-2-(S)-pyrrolidinyl)-methoxy)pyridine;

6-hydroxymethyl-3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine;

3-((trans-1,5-dimethyl-2-(S)-pyrrolidinyl)methoxy)pyridine;

3-((cis-4-cyano-1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine;

3-((cis-5-n-butyl-1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine;

3-((cis-4-fluoromethyl-1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine;

3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)-5-nitro-pyridine;

3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)-5-amino-pyridine;

3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)-5-methylamino-pyridine;

3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)-5-methylamino-pyridine;

3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)-5-acetylamino-pyridine;

3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)-5-methoxy-pyridine;

3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)-5-cyano-pyridine;

3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine-5-carboxylic acid,methyl ester;

3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine-5-carboxylic acid;

3-(2-(2-(S)-pyrrolidinyl)ethoxy)pyridine;

3-(2-(1-methyl-2-(S)-pyrrolidinyl)ethoxy)pyridine;

3-(2-(2-(S)-pyrrolidinyl)ethoxy)-6-chloropyridine;

3-(2-(1-methyl-2-(S)-pyrrolidinyl)ethoxy)-6-chloropyridine;

3-(2-(S)-pyrrolidinylmethylthioxy)-6-chloropyridine; and

3-(1-methyl-2-(S)-pyrrolidinylmethylthioxy)-6-chloropyridine;

or a pharmaceutically-acceptable salt or prodrug thereof.

In another embodiment of the instant invention are compounds of formula(I) or their pharmaceutically-acceptable salts or prodrugs, wherein thechiral center is of the (R) configuration.

Representative of the compounds of the invention wherein the chiralcenter is of the (R) configuration are:

3-((1-methyl-2-(R)-pyrrolidinyl)methoxy)-5-trifluoromethylpyridine;

2-((1-methyl-2-(R)-pyrrolidinyl)methoxy)-6-chloropyridazine; and

3-(2-(R)-pyrrolidinylmethoxy)-5-trifluoromethylpyridine,

or a pharmaceutically-acceptable salt or prodrug thereof.

The present invention is also directed to pharmaceutical compositionscomprising a therapeutically-effective amount of a compound of formula(I) and a pharmaceutically-acceptable carrier or diluent.

In yet another aspect of the present invention is provided the use oftherapeutically-effective pharmaceutical compositions to selectivelycontrol neurotransmitter release in mammals.

In yet another aspect of the invention is provided the use of3-(1-methyl-2-(S)-pyrrolidinylmethoxy)quinoline,4-(1-methyl-2-(S)-pyrrolidinylmethoxy)-isoquinoline, and3-(2-(R)-pyrrolidinylmethoxy)quinoline as agents useful in selectivelycontrolling neurotransmitter release in mammals.

Certain compounds of this invention may possess one or more asymmetriccenters and may exist in optically active forms. Additional asymmetriccenters may be present in a substituent group, such as an alkyl group.Pure cis-isomers and pure trans-isomers, racemic mixtures of theisomers, and mixtures thereof are intended to be within the scope ofthis invention. In particular, the stereochemistry at the 2-position andthe point of attachment of R³, as shown in Formula (I), mayindependently be either (R) or (S), unless specifically noted otherwise.Chiral forms of certain compounds of this invention are contemplated andare specifically included within the scope of this invention.

Throughout the specification and appended claims, the following termshave the definitions ascribed:

"C₁ -C₃ -alkyl" and "CC₁ -C₆ -alkyl" refer to branched orstraight-chain, unsubstituted alkyl groups-comprising one-to-three orone-to-six carbon atoms, including, but not limited to, methyl, ethyl,n-propyl, isopropyl, n-butyl, t-butyl, sec-butyl or isobutyl, oradditionally, for C₁ -C₆ -alkyl, neopentyl or n-hexyl and the like.

"C₁ -C₃ -alkoxyl" refers to branched or straight-chain, unsubstitutedalkyl groups comprising one-to-three or one-to-six carbon atoms,including, but not limited to, methyl, ethyl, n-propyl, isopropyl,n-butyl, t-butyl, sec-butyl or isobutyl, attached to an oxygen linkingatom.

"C₁ -C₃ -alkylamino" refers to a branched or straight-chain,unsubstituted alkyl group comprising one-to-three carbon atoms,including methyl, ethyl, n-propyl, or isopropyl, attached to an NHlinking group.

Di(C₁ -C₃ -alkyl)amino refers to two C₁ -C₃ -alkylamino groups, asdefined above, attached to an NH linking group.

"3-Azaaryloxy", as used herein, refers to a 6-membered aromaticcompounds containing 1 or 2 nitrogen atoms, including, but not limitedto pyridine, pyridazine, pyrazine, and pyrimidine, attached to anothermoiety of the molecule at a 3-position, counting from a N atom.

"Azacycloalkyl", as used herein, refers to a saturated monocycliccompound having one nitrogen atom and 3-to-5 carbon atoms in the ring,including azetidine, pyrrolidine and piperidine.

"Substituted-3-azaaryloxy", as used herein, refers to a 6-memberedaromatic compounds containing 1 or 2 nitrogen atoms, including, but notlimited to pyridine, pyridazine, pyrazine, and pyrimidine, attached toanother-moiety of the molecule at a 3-position, counting from a N atom,which may be mono-substituted, by groups such as, for example, hydroxyl,Br, Cl, F, CF₃, C₁ -C₃ -alkyl, C₁ -C₃ -alkoxy, amino, acetylamino, C₁-C₃ -alkylamino, di(C₁ -C₃ -alkyl)amino, cyano, CO-OH, CO-C₁ -C₃ -alkyl,CO-NH₂, CO-NH-C₁ -C₃ -alkyl,CO-N-(C₁ -C₃ -alkyl)₂, or CO-NH-benzyl.

The term, "prodrug", refers to compounds that are rapidly transformed invivo to yield the parent compounds of Formula (I), as for example, byhydrolysis in blood. T. Higuchi and V. Stella provide a thoroughdiscussion of the prodrug concept in Prodrugs as Novel Delivery Systems,Vol. 14 of the A.C.S. Symposium Series, American Chemical Society(1975). Examples of esters useful as prodrugs for compounds containingcarboxyl groups may be found on pages 14-21 of Bioreversible Carriers inDrug Design: Theory and Application, edited by E. B. Roche, PergamonPress (1987).

The term, "prodrug ester group", refers to any of several ester-forminggroups that are hydrolyzed under physiological conditions. Examples ofprodrug ester groups include pivoyloxymethyl, acetoxymethyl, phthalidyl,indanyl and methoxymethyl, as well as other such groups known in theart.

The term, "administration", of the cholinergic agent or composition, asused herein, refers to systemic use as when taken orally, parenterally,by inhalation spray, by nasal, rectal or buccal routes, or topically asointments, pastes, creams, lotions, gels, powders, solutions, sprays,inhalants or transdermal patches in dosage form unit formulationscontaining conventional nontoxic pharmaceutically acceptable carriers,adjuvants and vehicles as desired.

The term "parenteral", as used herein, includes intravenous,intramuscular, intraperitoneal, intrasternal, subcutaneous andintraarticular injection as well as via infusion techniques.

By "pharmaceutically-acceptable", it is meant those salts, amides andesters which are, within the scope of sound medical judgement, suitablefor use in contact with the tissues of humans and animals without unduetoxicity, irritation, allergic response and the like, and arecommensurate with a reasonable benefit/risk ratio, effective for theirintended use in the treatment of psychological, neurological,cardiovascular and addictive behavior disordersPharmaceutically-acceptable salts are well known in the art. Forexample, S. M. Berge, et al. describe: pharmaceutically-acceptable saltsin detail in J. Pharmaceutical Sciences, 66: 1-19, 1977. The salts maybe prepared in situ during the final isolation and purification of thecompounds of Formula (I), or separately by reacting the free basefunction with a suitable organic acid. Representative acid additionsalts include hydrochloride, hydrobromide, sulfate, bisulfate, acetate,oxalate, valerate, oleate, palmitate, stearate, laurate, borate,benzoate, lactate, phosphate, toluenesulfonate, methanesulfonate,citrate, maleate, fumarate, succinate, tartrate, ascorbate,glucoheptonate, lactobionate, lauryl sulfate salts and the like.Representative alkali or alkaline earth met al salts include sodium,calcium, potassium, magnesium salts and the like. Examples ofpharmaceutically-acceptable, nontoxic amides of the compounds of FormulaI include amides derived from C₁ -C₆ -alkyl-carboxylic acids wherein thealkyl groups are straight- or branched-chain, aromatic carboxylic acidssuch as derivatives of benzoic acid and heterocyclic carboxylic acids,including furan-2-carboxylic acid or nicotinic acid. Amides of thecompounds of Formula I may be prepared according to conventional methodsand include amino acid and polypeptide derivatives of the amines ofFormula I.

As used herein, the term, "pharmaceutically-acceptable carriers", meansa non-toxic, inert solid, semi-solid or liquid filler, diluent,encapsulating material or formulation auxiliary of any type. Someexamples of the materials that may serve as pharmaceutically-acceptablecarriers are sugars, such as lactose, glucose and sucrose; starches suchas corn starch and potato starch; cellulose and its derivatives such assodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tagacanth; malt; gelatin; talc; excipients such as cocoa butterand suppository waxes; oils such as peanut oil, cottonseed oil,safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols,such as propylene glycol; polyols such as glycerin, sorbitol, mannitoland polyethylene glycol; esters such as ethyl oleate and ethyl laurate;agar; buffering agents such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol and phosphate buffer solutions, as well as othernon-toxic compatible substances used in pharmaceutical formulations.Wetting agents, emulsifiers and lubricants such as sodium lauryl sulfateand magnesium stearate, as well as coloring agents, releasing agents,coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants may also be present in the composition,according to the judgement of the formulator. Examples ofpharmaceutically-acceptable antioxidants include water-solubleantioxidants, such as ascorbic acid, cysteine hydrochloride, sodiumbisulfite, sodium metabisulfite, sodium sulfite, and the like;oil-soluble antioxidants, such as ascorbyl palmitate, butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propylgallate, alpha-tocopherol and the like; and the met al chelating agentssuch as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol,tartaric acid, phosphoric acid and the like.

By a "therapeutically-effective amount" of the cholinergic channelligand agent, is meant a sufficient amount of the compound to treatcholinergically-related disorders at a reasonable benefit/risk ratioapplicable to obtain a desired therapeutic response. It will beunderstood, however, that the total daily usage of the compounds andcompositions of the present invention will be decided by the attendingphysician within the scope of sound medical judgement. The specifictherapeutically effective dose level for any particular patient willdepend upon a variety of factors including the disorder being treatedand the severity of the disorder; activity of the specific compoundemployed; the specific composition employed; the age, body weight,general health, sex and diet of the patient; the time of administration,route of administration, and rate of excretion of the specific compoundemployed; the duration of the treatment; drugs used in combination orcoincidentally with the specific compound employed; and like factorswell known in the medical arts. Total daily dose of the compounds ofthis invention administered to a host in single or divided doses may bein amounts as determined by the attending physician, typically, forexample, in amounts of from about 0.001 to 100 mg/kg body weight dailyand preferably 0.01 to 10 mg/kg/day. Dosage unit compositions maycontain such amounts of submultiples thereof to make up the daily dose.

The present invention includes one or more of the compounds of formula(1) prepared and formulated with one or more non-toxicpharmaceutically-acceptable compositions, as described below.

Compositions suitable for parenteral injection may comprisepharmaceutically-acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and nonaqueous carriers, diluents, solventsor vehicles include water, ethanol, polyols (propylene glycol,polyethylene glycol, glycerol, and the like), suitable mixtures thereof,vegetable oils (such as olive oil) and injectable organic esters such asethyl oleate. Proper fluidity may be maintained, for example, by the useof a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersions, and by the use of surfactants.

These compositions may also contain adjuvants such as preserving,wetting, emulsifying, and dispersing agents. Prevention of the action ofmicroorganisms may be ensured by various antibacterial and antifungalagents, for example, parabens, chlorobutanol, phenol, sorbic acid, andthe like. It may also be desirable to include isotonic agents, forexample, sugars, sodium chloride and the like. Prolonged absorption ofthe injectable pharmaceutical form may be brought about by the use ofagents delaying absorption, for example, aluminum monostearate andgelatin.

If desired, and for more effective distribution, the compounds may beincorporated into slow-release or targeted-delivery systems, such aspolymer matrices, liposomes, and microspheres. They may be sterilized,for example, by filtration through a bacteria-retaining filter, or byincorporating sterilizing agents in the form of sterile solidcompositions, which may be dissolved in sterile water, or some othersterile injectable medium immediately before use.

Solid dosage forms for oral administration may include capsules,tablets, pills, powders, and granules In such solid dosage forms, theactive compound is admixed with at least one inert customary excipient(or carrier), such as sodium citrate or dicalcium phosphate, andadditionally (a) fillers or extenders, as for example, starches,lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, asfor example, carboxymethylcellulose, alginates, gelatin,polyvinylpyrrolidone, sucrose and acacia; (c) humectants, as forexample, glycerol; (d) disintegrating agents, as for example, agar-agar,calcium carbonate, potato or tapioca starch, alginic acid, certaincomplex silicates and sodium carbonate; (e) solution retarders, as forexample paraffin; (f) absorption accelerators, as for example,quaternary ammonium compounds; (g) wetting agents, as for example, cetylalcohol and glycerol monostearate; (h) adsorbents, as for example,kaolin and bentonite; and (i) lubricants, as for example, talc, calciumstearate, magnesium stearate, solid polyethylene glycols, sodium laurylsulfate or mixtures thereof. In the case of capsules, tablets and pills,the dosage forms may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules, using such excipients as lactoseor milk sugar, as well as high molecular weight polyethylene glycols,and the like.

Solid dosage forms such as tablets, dragees, capsules, pills andgranules may be prepared with coatings and shells, such as entericcoatings and others well known in this art. They may contain pacifyingagents, and may also be of such composition that they release the activecompound or compounds in a certain part of the intestinal tract in adelayed manner. Examples of embedding compositions which may be used arepolymeric substances and waxes.

The active compounds may also be in micro-encapsulated form, ifappropriate, with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration includepharmaceutically-acceptable emulsions, solutions, suspensions, syrupsand elixirs, In addition to the active compounds, the liquid dosageforms may contain inert diluents commonly used in the art, such as wateror other solvents, solubilizing agents and emulsifiers, as for example,ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethylformamide, oils, in particular, cottonseed oil, groundnut oil,corn germ oil, olive oil, castor oil and sesame oil, glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan or mixtures of these substances, and the like.

Besides such inert diluents, these liquid dosage forms may also includeadjuvants, such as wetting agents, emulsifying and suspending agents,sweetening, flavoring and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspendingagents, as for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, or mixtures of thesesubstances, and the like.

Compositions for rectal or vaginal administrations are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax, which are solidat ordinary temperatures but liquid at body temperature and therefore,melt in the rectum or vaginal cavity and release the active component.

Dosage forms for topical or transdermal administration of a compound ofthis invention further include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or transdermal patches.Transdermal administration via a transdermal patch is a particularlyeffective and preferred dosage form of the present invention. The activecomponent is admixed under sterile conditions with apharmaceutically-acceptable carrier and any needed preservative, buffersor propellants as may be required. It is known that some agents mayrequire special handling in the preparation of transdermal patchformulations. For example, compounds that are volatile in nature mayrequire admixture with special formulating agents or with specialpackaging materials to assure proper dosage delivery. In addition,compounds which are very rapidly absorbed through the skin may requireformulation with absorption-retarding agents or barriers. Ophthalmicformulations, is eye ointments, powders and solutions are alsocontemplated as being within the scope of this invention.

The present compounds may also be administered in the form of liposomes.As is known in the art, liposomes are generally derived fromphospholipids or other lipid substances. Liposomes are formed by mono-or multi-lamellar hydrated liquid crystals that are dispersed in anaqueous medium. Any non-toxic, physiologically-acceptable andmetabolizable lipid capable of forming liposomes may be used. Thepresent compositions in liposome form may contain, in addition to thecompounds of the present invention, stabilizers, preservatives,excipients, and the like. The preferred lipids are the phospholipids andthe phosphatidyl cholines (lecithins), both natural and synthetic.Methods to form liposomes are known in the art. See, for example,Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, NewYork, N. Y., (1976), p 33 et seq.

In order to reduce unwanted peripherally-mediated side-effects, it isadvantageous, but not essential, to incorporate into the composition aperipherally-acting anti-cholinergic such as N-methylscopolamine,N-methylatropine, propantheline, methantheline, or glycopyrrolate.

Compounds of the invention which have one or more asymmetric carbonatoms may exist as the optically-pure enantiomers, pure diastereomers,mixtures of enantiomers, mixtures of diastereomers, racemic mixtures ofenantiomers, diastereomeric racemates or mixtures of diastereomericracemates. It is to be understood that the present invention anticipatesand includes within its scope all such isomers and mixtures thereof. Theterms "R" and "S" used herein are configurations as defined in IUPAC1974 Recommendations for Section E. Fundamental Stereochemistry, PureAppl. Chem., 1976, 45: 13-30.

The compounds of the present invention may be synthesized as shown inreaction schemes I and II presented below using the reactions andtechniques described in this section. The reactions are performed in asolvent appropriate to the reagents and materials employed are suitablefor the transformation being effected. It is understood by those skilledin the art of organic synthesis that the functionality present on theheterocyclic ring and other portions of the molecule must be consistentwith the chemical transformation proposed. This will, on occasion,necessitate judgment by the routineer as to the order of syntheticsteps, protecting groups required, and deprotection conditions.Substituents on the starting materials may be incompatible with some ofthe reaction conditions required in some of the methods described, butalternative methods and substituents compatible with the reactionconditions will be readily apparent to skilled practitioners in the art.The use of nitrogen-protecting groups is well known in the art forprotecting amino groups against undesirable reactions during a syntheticprocedure and many such protecting groups are known, cf, for example, T.W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2ndedition, John Wiley & Sons, New York (1991). ##STR8##

In accordance with Reaction Scheme I, compounds of Formula (I) wherein Dis selected from option (ii) are prepared by reacting a2-carboxyl-substituted azacycloalkyl compound (1), wherein n is asdescribed above, R³ is H and wherein the Y is a C₁ -C₃ -alkyl or asuitable protecting group, such as BOC or CBZ, for example, which maysubsequently be removed and replaced with H, allyl, or C₁ -C₃ -alkyl, isconverted to the hydroxymethyl compound of formula (2) with a suitablereducing agent, such as Red-Al®, borane/THF, borane/methyl sulfide orLiAlH₄, for example. Compound (2) is reacted with an appropriate3-hydroxypyridine compound, which is substituted with the appropriate R⁴group, wherein R⁴ is as described above, or is an appropriatelyprotected R⁴ group, wherein the protecting group may be removed afterthe coupling reaction, in the presence of triphenylphosphine and DEAD asdescribed by O. Mitsunobu (Synthesis, 1981: 1) to form the pyridinecompound of formula (3). This compound is then treated with a reagentsuitable for removing the N-protecting group, such as trifluoroaceticacid, HCl in glacial acetic acid or HBr in acetic acid, for example, toform the unprotected compound (4). The ring nitrogen is then alkylated,with for example, treatment with alkyl halide in the presence of a base,formaldehyde in formic acid, or with an aldehyde and sodiumcyanoborohydride, in an alcohol solvent, such as methanol, ethanol orisopropanol, or by reaction with the appropriate allylating reagent,such as, for example, allyl bromide, to give the desired compound (5),wherein R¹ is as described above, which is compound (I), wherein A isselected from option (i) and D is selected from option (ii).

Alternately, compound (2) may be oxidized using a suitable mildoxidizing agent such as DMSO/pyridineΩSO₃, pyridinium chlorochromate orDMSO/oxalyl chloride, for example, to afford the aldehyde (6). Thealdehyde is then reacted with a suitable organometallic nucleophile, forexample, a Grignard reagent, to afford the alcohol (7), wherein R² is asdescribed above. The alcohol is then reacted as described above with a3-hydroxypyridine and carried through the same series of reactions asdescribed above, starting with compound (2) and leading to compounds(3), (4) and (5), to give the compounds (8), (9) and (10), wherein R¹ isas described above.

In accordance with Reaction Schemes II and III are prepared compounds(5) and (10) of Scheme I, wherein certain desirable R⁴ groups are addedafter the condensation step by conversion of a suitable precursor groupto the desired group. In Scheme II, the appropriate intermediatecompound (2) or (7) is reacted in an anhydrous solvent in the presenceof a strong base, such as NaH, for example, with 3,5-dinitropyridine(11) to give compound (12). Compound 7 may also be reacted with compound11A to give the compound (13). Compound 13 may then be reacted with NH₃in the presence of CuBr to give the compound (13A). Compound (13A) maythen be reacted with the appropriate. C₁ -C₃ -alkyl iodide or acetylchloride under standard conditions known to those skilled in the art togive the compound (14) wherein R⁵ is C₁ -C₃ -alkyl or acetyl. ##STR9##

In Reaction Scheme III, the appropriate intermediate compound (2) or (7)is reacted in an anhydrous solvent in the presence of a strong base,such as NaH, for example, with 3,5-dibromopyridine N-oxide (15) to givecompound (16), wherein R² is H or is as described above. Compound 16 maybe reacted with sodium methoxide in methanol and the intermediateproduct reacted with hydrogen in the presence of Raney nickel to givecompound (17). Alternately, compound (16) may be reacted with NaCN inDMF and water according to standard procedures and the intermediateproduct reacted with hydrogen in the presence of laney nickel to givecompound (17A). Compound (13) may be reacted with a carboxylatingreagent, such as palladium triphenylphosphine dichloride and CO in thepresence of methanol and triethylamine, to give the ester compound (18).The ester (18) may be hydrolyzed by standard methods to give thecarboxylic acid compound (19). ##STR10##

In accordance with Reaction Scheme IV, the compound (2) wherein Y is Hor is a C₁ -C₃ -alkyl or a suitable protecting group, such as BOC orCBZ, for example, is reacted with 3,6-dichloropyridazine,2-chloropyrazine, 3-chloroquinoline, 5-chloroisoquinoline, bromothiazoleor 5-bromopyrimidine, in the presence of a strong base, such as sodiumhydride, or in the presence of K₂ CO₃, CuBr and PPh₃, in an inertsolvent, such as THF, to afford compound (20), where D is3-(6-chloropyridazinyl), 2-pyrazinyl, 3-quinolinyl, 2-thiazolyl, or5-pyrimidinyl, respectively. Compound (20) is then carried through thesame series of reactions as described in Scheme I above (starting withcompound (3) and leading to compounds (4) and (5)) to give the compounds(21) and (22), wherein R¹ is as described above. Alternately, compound(7) is reacted with one of the reagents as described for compound (2)above to give compound (23). Compound (23) is then carried through thesame series of reactions as described in Scheme 1 above (starting withcompound (8) and leading to compounds (9) and (10)) to give thecompounds (24) and (25), wherein R¹ and R2 are as described above.##STR11##

In accordance with Reaction Scheme V, wherein is described thepreparation of precursors of the "D" portion of the compounds of formula(I), wherein D is selected from option (ii) wherein R⁴ is 4substitutedC₁ -C₃ -alkyl or Hal group, as defined above, the 3-hydroxypyridine (26)is protected by reaction with dimethylaminocarbonyl chloride to give thecompound (27). It is possible to place the Hal substitutent on compound(27) by reaction with sec-BuLi followed by reagents represented by theformula Hal-Z, wherein Z is a leaving group, such as 1,2-dibromoethane,N-halosuccinimide, or molecular halogen, for example, to give compound(28). By removing the protecting group from compound (28) with a reagentsuch as sodium methoxide, for example, the desired compound (29) isproduced. Alternately, where it is desired to place an alkyl substituentupon the ring, compound (27) is reacted with sec-BuLi followed by andalkyl halide, such as alkyl bromide or alkyl iodide, for example, togive compound (30), which is then deprotected with a reagent such assodium methoxide, for example, to give the desired compound (31).##STR12##

In accordance with Reaction Scheme VI, the compound (32) may be reacted10 according to the alternate reaction pathways shown for compounds (2)or (7) in Schemes I and II to give the desired compound (33). TheN-alkyl group, wherein the alkyl group is C₁ -C₆ -alkyl, is added tocompound (33) by reaction with NaH and the appropriate alkyl iodide inanhydrous THF to give compound (34). Compound (34) is treated with LDAand E-X, wherein X is a leaving group and E is the appropriate precursorgroup of R³, as defined above, (except in the case wherein R³ is C₁ -C₃-alkoxy, in which case the first reaction produces an alcohol which isthen reacted under standard Williamson ether synthesis conditions togive the ether), such as an oxaziridine, formaldehyde, a halomethylether, N-halo-succinimide, or molecular halogen, for example, to givethe substituted compound (35), wherein R³ is as described above, whichby reducing with BH₃ followed by treatment with CsF gives the desiredcompound (36).

In accordance with Reaction Scheme VII are synthesized the compounds offormula (I), wherein A is selected from option (i), wherein R³ thereinrepresents the appropriate 5-substituent group, wherein R³ is asdescribed above, compound (34) is reacted with an C₁ -C₃ -alkyl Grignardreagent followed by NaBH₃ CN to give the compound (37). When compound(34) is reacted with a C₁ -C₃ -alkyl Grignard reagent followed by NaBH₃CN, the compound (39) is prepared, wherein R³ is as described above, andmay be two substituent groups.

IN VITRO DETERMINATION OF STRIATAL DOPAMINE RELEASE AND NEURONALNICOTINIC RECEPTOR BINDING POTENCIES AND SELECTIVITY

For the purpose of demonstating that compounds of the inventionstimulate dopamine release or inhibit nicotine-evoked dopamine release,a striatal dopamine release assay was utilized. The protocol for thisprocedure follows below.

A. Protocol for Determination of Striatal Dopamine Release.

nAChR evoked release of ring-2,5,6-³ H!-dopamine (24.4 Ci/mmol) wasmeasured in superfused rat striatal slices. Striata were dissected fromtwo male Sprague-Dawley rats per experiment and sliced 0.35×0.25 mm by aMcIlwain Tissue Chopper (Brinkman Instrument Co., Westbury, N.Y.). Aftertwo washes with Krebs-HEPES buffer (137 mM NaCl, 4.7 mM KCl, 1 mM MgSO₄,2.5 mM CaCl₂, 1.25 mM NaH₂ PO₄, 10 mM glucose, 15 mM HEPES-NaOH, pH 7.4,containing 10 μM pargyline and 10 μM ascorbic acid), slices werepreincubated for 10 minutes at 3720 C. under 95%/5% O₂ /CO₂. Afterreplacing the buffer, slices were labeled with 100 mM ³ H!-dopamine for25 min in Krebs-HEPES at 3720 C. Aliquots of slices were placed in 18superfusion chambers of a Brandel SP2000 superfusion apparatus (Brandel,Gaithersberg, Md.). Following 47 minutes of washout, slices were exposedto agonist at various concentrations for4 minutes. Antagonists orinhibitors, when present were introduced 4 minutes prior to and duringagonist exposure. Collected fractions were counted in 5 mL of Ecolume.Tissue was recovered from superfusion chambers, solubilized with 1 mL ofSolvable™ (DuPont-NEN) and counted in 15 mL of Ecolume. Fractionalrelease of ³ H!-dopamine was calculated from radioactivity abovebaseline as a fraction of total radioactivity. Relative potencies werecalculated using the release evoked by 100 nM (-)-nicotine as astandard.

For the purpose of identifying compounds as cholinergic agents which arecapable of interacting with cholinergic channel receptors in the brain,a ligand-receptor binding assay was carried out as the initial screen.Compounds of the present invention were effective at interacting withneuronal nicotinic cholinergic receptors as assayed for their ability(compared to (-)-nicotine) to displace radioligand from neuronalnicotinic cholinergic channel receptors labeled with 3H!-cytisine ( ³H!-CYT).

The ability of the compounds of the invention to interact withcholinergic channel receptors and thereby to activate or inhibitneurotransmitter release can be demonstrated in vitro using thefollowing protocol.

B. Protocol For Determination of Nicotinic Cholinergic Channel ReceptorBinding Potencies of Ligands

Binding of ³ H!-cytisine ( ³ H!-CYT) to nicotinic receptors wasaccomplished using crude synaptic membrane preparations from whole ratbrain (Pabreza et al., Molecular Pharmacol., 1990, 39:9). Washedmembranes were stored at -80° C. prior to use. Frozen aliquots wereslowly thawed and resuspended in 20 volumes of buffer (containing: 120mM NaCl, 5 mM KCl, 2 mM MgCl₂, 2 mM CaCl₂ and 50 mM Tris-Cl, pH 7.4 @4°C.). After centrifuging at 20,000×g for 15 minutes, the pellets wereresuspended in 30 volumes of buffer. Homogenate (containing 125-150 mgprotein) was added to triplicate tubes containing concentrations of testcompound and ³ H!-CYT (1.25 nM) in a final volume of 500 μL. Sampleswere incubated for 60 minutes at 4° C., then rapidly filtered throughWhatman GF/B filters presoaked in 0.5% polyethylimine using 3×4 mL ofice-cold buffer. The filters are counted in 4 mL of Ecolume® (ICN).Nonspecific binding was determined in the presence of 10 μM (-)-nicotineand values were expressed as a percentage of total binding. IC₅₀ valueswere determined with the RS-1 (BBN) nonlinear least squarescurve-fitting program and IC₅₀ values were converted to Ki values usingthe Cheng and Prusoff correction (Ki=IC₅₀ /(1+ ligand!/Kd of ligand).Alternately, data were expressed as a percentage of the total specificbinding. The results (shown in Tables 1 and 2) suggest that thecompounds of the present invention have high affinity for the neuronalnicotinic cholinergic channel receptor.

D. Protocols for the Determination of Cholinergic Channel Activation inPC12 Cells.

The cholinergic channel activator properties of Example 9 wereinvestigated in PC12 cells using the whole-cell patch-clamp approach tomeasure current flow through ligand-gated membrane channels. Theelectrophysiological approach demonstrates clear agonist activity of theactivator, and indicates that this is due to direct activation ofcholinergic ligand-gated channels.

Data in Table 1 show that compounds of the present invention bind tohigh-affinity nicotine receptors and control dopamine release. Thisfinding is in agreement with the results of others who have linkeddopamine release to binding at nicotinic receptors (cf., for example,Lippiello and Caldwell, U.S. Pat. No. 5,242,935, issued Sep. 7, 1993;Caldwell and Lippiello, U.S. Pat. No. 5,248,690, issued Sep. 28, 1993;and Wonnacott et al., Prog. Brain Res., 79: 157-163 (1989)).

                  TABLE 1    ______________________________________    Binding to Neuronal Nicotinic Receptors and    Control of Dopamine Release    Example     Receptor Binding                            Dopamine Release    number      Ki (nM)     relative to Nicotine ≠    ______________________________________    (-)-nicotine                0.69        1.0     1          23          0.08*     4          0.2         1.0*     8          33          0.55*     9          0.05        1.0*    10          0.25        1.0*    14          0.14        1.0**    16          0.6         1.0**    17          16.7        0.7*    18          0.28        1.0***    19          1.47        0.78***    31          0.7         0.15*    33          0.2         0.62**    37          0.5         0.8*    38          13          0.6*    46          4           0.85*    52          0.04        1.0*    59          4.5         0.7*    103         18.4        0.3*    ______________________________________     ≢ example concentration: *= 10 μM; **= 1 μM; ***= 0.1 μ

Nicotinic binding data of additional compounds of the present inventionare given in Table 2.

                  TABLE 2    ______________________________________    Binding to Neuronal Nicotinic Receptors    Example       Receptor Binding    number        Ki (nM)    ______________________________________    (-)-nicotine  0.69     2            0.17     3            20     5            87     6            6.7     7            0.44    11            110    12            29    13            65    15            0.13    20            341    21            23    22            25    23            78.3    24            4.2    25            14.7    26            76    27            5.8    28            0.23    29            1.3    30            129    32            110    34            11    35            39    36            26    39            0.04    40            0.05    41            9.9    42            342    43            18.6    44            1.8    45            0.075    47            23    48            30    49            66    50            5.6    51            4.5    53            28    54            78    55            0.63    56            9.2    57            17    58            5.3    60            51    61            1.3    62            0.5    63            1.4    64            224    65            0.6    66            4    67            0.2    68            4.5    69            2.1    70            0.6    71            0.1    72            110    73            0.48    74            59    75            0.32    76            12.8    77            0.1    78            5.77    79            42.8    80            1.9    81            9.3    82            72.4    83            73.1    84            2.41    85            16    86            1.43    87            0.11    88            10.4    89            91.2    90            18.4    91            1.47    92            141    94            0.5    102           34.9    103           18.4    105           33.1    108           4.9    109           0.024    110           0.75    ______________________________________

The following examples, which are provided for illustration and notlimitation of the invention, will serve to further illustratepreparation of the novel compounds of the invention and their biologicalactivity. Thin-layer chromatography (TLC) was performed on 0.25 mm E.Merck precoated silica gel plates (60 F-254). Flash chromatography wasperformed on 200-400 mesh silica gel (E. Merck), while columnchromatography was performed on 70-230 mesh silica gel (E. Merck).

The following abbreviations are used: THF for tetrahydrofuran, DMF forN,N-dimethylformamide, D₂ O for deuterium oxide, CDCl₃ fordeuterochloroform, DMSO-d₆ for deuterodimethylsulfoxide, BOC fort-butyloxycarbonyl, CBZ for benzyloxycarbonyl, Bz for benzyl, MS formethanesulfonyl, PAW for pyridine/acetic acid/water (20:6:11), DCC fordicyclohexylcarbodiimide, DIBAL for diisobutylaluminum hydride, DIEA fordiisopropylethylamine, DPPA for diphenylphosphoroazidate, dppp for1,3-bis(diphenylphosphino)propane, EDCI for1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride, EtOH forethanol, IBCF for isobutyl chloroformate, HOAc for acetic acid, HOBT for1-hydroxybenzotriazole, LAH for lithium aluminum hydride, NH₄ OAc forammonium acetate, NMM for N-methylmorpholine, TEA for triethylamine.

EXAMPLE 1

3-((1-methyl-2-(R)-pyrrolidinyl)methoxy)pyridine hydrochloride

1a. 3-((1-methyl-2-(R)-pyrrolidinylmethoxy)pyridine

To a solution of triphenylphosphine (509 mg, 1.94 mmol) in 10 mL oftetrahydrofuran at room temperature was added diethyl azodicarboxylate(DEAD) (0.35 mL, 1.94 mmol) dropwise with stirring. After stirring atroom temperature for 30 minutes, (R)-1-methyl-2-pyrrolidinemethanol(Aldrich Chemical Co., 150 mg, 1.30 mmol) and 3-hydroxypyridine (AldrichChemical Co., 185 mg, 1.94 mmol) were added to the reaction mixture. Theresultant solution was then stirred at room temperature overnight. Afterall of the starting material was consumed, the organic solvent wasevaporated in vacuo. The residue was purified by column silica gelchromatography eluting with chloroform:methanol (10: 1) to provide 76 mg(21% yield) of the title compound. MS (DCI/NH₃) m/e 193 (M+H)⁺. ¹ H NMR(CDCl₃, 300 MHz) δ: 8.32 (t, J=1.5 Hz, 1H), 8.22 (t, J=3 Hz, 1H)7.24-7.2 (m, 2H), 4.14-4.05 (dd, J=9, 6 Hz, 1H), 4.00-3.93 (dd, J=9, 6Hz, 1H), 3.24-3.14 (m, 1H), 2.81-2.7 (m, 1H), 2.54 (s, 3H), 2.44-2.31(m, 1H), 2.14-2.00 (m, 1H), 1.96-1.71 (m, 3H).

1b. 3-((1-methyl-2-(R)-pyrrolidinyl)methoxy)pyridine hydrochloride

The compound from step la above (76 mg, 0.4 mmol) was dissolved inethanol. Hydrochloric acid in diethyl ether was added dropwise to astirring solution of base at ambient temperature. The resultant whiteprecipitate was then collected by evaporation of solvent and trituratedwith three portions of diethyl ether. The hygroscopic solid was obtainedin 50% yield (53 mg). MS (DCI/NH₃) m/e 193 (M+H)⁺. ¹ H NMR (D₂ O, 300MHz) δ: 8.43 (br s, 1H), 8.33 (d, J=5.6 Hz, 1H), 7.88-7.82 (m, 1H), 7.72(dd, J=8.50, 5.15 Hz, 1H), 4.59 (dd, J=11, 3 Hz, 1H), 4.42 (dd, J=11.4,6.2 Hz, 1H), 4.17-4.25 (m, 1H), 4.05-3.9 (m, 1H), 3.82-3.74 (m, 1H),3.34-3.22 (m, 1H), 3.04 (s, 3H), 2.42-2.36 (m, 1H), 2.26-2.06 (m, 3H).Analysis calculated for C₁₁ H₁₆ N₂ OΩHClΩ0.2 H₂ O: C, 49.15; H, 6.90; N,10.42; Found: C, 48.90; H, 7.17; N, 10.89. α!²⁵ D=+6.54° (c=1, MeOH).

EXAMPLE 2

3-(2-(R)-pyrrolidinylmethoxy)pyridine dihydrochloride

2a. 3-(1-t-butoxycarbonyl-2-(R)-pyrrolidinylmethoxy) pyridine

To a solution of triphenylphosphine (1.24 g, 4.74 mmol) in 20 mL oftetrahydrofuran at room temperature was added diethyl azodicarboxylate(0.746 mL, 4.74 mmol) dropwise with stirring. After stirring at roomtemperature for 30 minutes, (R)-1-t-butoxycarbonyl-2-pyrrolidinemethanol(350 mg, 3.16 mmol) and 3-hydroxypyridine (450 mg, 4.74 mmol) were addedto the reaction mixture. The resultant solution was then stirred at roomtemperature overnight. After all of the starting material was consumed,the organic solvent was evaporated in vacuo. The residue was purified bysilica gel column chromatography. Elution with chloroform:methanol(10: 1) provided 518 mg of the title compound along with substantialamount of reduced DEAD reagent. MS (DCI/NH₃) m/e 279 (M+H)⁺.

2b. 3-(2-(R)-pyrrolidinylmethoxy)pyridine

To a solution of the compound of Example 2a in 2 mL of methylenechloride solution was added 2 mL of trifluoroacetic acid. The resultantsolution was stirred at room temperature for 2.5 hour. Evaporation ofboth solvent and trifluoroacetic acid gave a brown oil which wasbasified with saturated ammonium hydroxide solution. This oil waspurified by silica gel column chromatography. Elution with a mixture ofchloroform:methanol: ammonium hydroxide (101:0.1) provided the desiredproduct MS (DCI/NH₃) m/e 179 (M+H)⁺. ¹ H NMR (D₂ O,300 MHz) δ: 8.33 (brs, 1H), 8.22 (m, 1H), 7.22(m, 2H), 3.82-4.03 (m, 2H), 3.50-3.61 (m, 1H),2.92-3.10(m, 2H), 1.70-2.10 (m, 4H), 1.51-1.66 (m, 1H).

2c. 3-(2-(R)-pyrrolidinylmethoxy)pyridine dihydrochloride

The compound from Example 2b (76 mg, 0.4 mmol) was dissolved in ethanol.Hydrochloric acid in diethyl ether was added dropwise to a stirringsolution of base at ambient temperature. The resultant white precipitatewas then collected by evaporation of solvent and triturated with threeportions of diethyl ether. The hygroscopic solid was obtained in 50%yield (53 mg). MS (DCI/NH₃) m/e 179 (M+H)⁺. ¹ H NMR (D₂ O,300 MHz) δ:8.43 (br s, 1H), 834 (br s 1H), 7.85(dd, J=8.80, 2.90 Hz, 1H), 7.72 (dd,J=8.80, 5.15 Hz, 1H), 4.54 (dd, J=11, 3.3 Hz, 1H), 4.32 (dd, J=10.6, 3.3Hz, 1H), 4.10-4.19 (m, 1H), 3.42 (t, J=7.5 Hz, 1H), 2.27-2.35 (m, 1H),2.06-2.21 (m, 2H), 1.90-2.02 (m, 1H). Anal. calc. for C₁₀ H₁₄ N₂ OΩ2.4HCl: C, 45.20; H, 6.22; N, 10.54; Found: C, 45.12; H, 6.00; N, 10.33.

EXAMPLE 3

2-((1-methyl-2-(S)-pyrrolidinyl)methoxy)pyrazine fumarate

3a. 2-((1-methyl-2-(S)-pyrrolidinyl)methoxypyrazine

(S)-(-)-1-Methyl-2-pyrrolidinemethanol (Aldrich Chemical Co., 0.5 g,4.34 mmol) was dissolved in anhydrous THF and brought to 020 C. NaH((80% dispersion in mineral oil), 131 g, 4.56 mmol) was added and thereaction mixture was allowed to warm to room temperature with stirring.After 30 minutes 2-chloropyrazine (0.497 g, 4.34 mmol) was added viasyringe. The mixture was stirred for 48 hours. The solvent was thenevaporated in vacuo and the mixture diluted with chloroform, washed withsaturated NaHCO₃ and a brine solution. The organic layer was then driedover MgSO₄. The resulting crude material was purified by flashchromatography (10% MeOH/CHCl₃) to give 0.81 g (97% yield) of the titlecompound as an oil. TLC R_(f) =0.3 (10%MeOH/CHCl₃). MS (DCI/NH₃) m/e 194is (M+H)⁺. ¹ HNMR(CDCl₃,300 MHz) δ: 8.24 (d, J=1.5 Hz, 1H), 8.11 (d, J=3Hz, 1H), 8.07 (dd, J=3, 1.5 Hz, 1H), 4.36 (dd, J=9, 6 Hz, 1H), 4.28 (dd,J=9, 6 Hz, 1H), 3.16-3.08 (m, 1H), 2.7-2.58 (m, 1H), 2.47 (s, 3H),2.34-2.24 (m, 1H), 2.08-1.93 (m, 1H), 1.91-1.67 (m, 31H).

3b. 2-((1-methyl-2-(S)-pyrrolidinyl)methoxy)pyrazine fumarate

The compound of step 3a was dissolved in anhydrous MeOH and brought to0° C. with stirring. Fumaric acid was dissolved in MeOH with sonicationand added dropwise to the base. The mixture was warmed to roomtemperature with stirring. After 30 minutes the solvent was evaporatedin vacuo and the remaining solid was triturated with anhydrous diethylether. The resulting white solid was vacuum filtered to yield. 0.117 g(50% yield) of product. m.p.=116-118° C. MS (DCI/NH₃) m/e 194 (M+H)⁺. ¹H NMR (D₂ O, 300 MHz) δ: 8.33 (d, J=1.1 Hz, 1H), 8.23-8.21 (m, 2H), 6.65(br s, 2H), 4.7&4.71 (dd, J=12.5, 3 Hz, 1H), 4.60-4.54 (dd, J=12.5, 6Hz, 1H), 3.98-3.9 (m, 114), 3.8-3.72 (m, 1H), 3.3-3.2 (m, 1H), 3.04 (s,3H), 2.45-2.32 (m, 1H), 2.28-2.01 (m, 3H). Analysis calculated for C₁₀H₁₅ N₃ OΩC₄ H₄ O₄ : C, 54.36; H, 6.19; N, 13.58; Found: C, 54.23; H,6.04; N, 13.58.

EXAMPLE 4

3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine fumarate

4a. 3-((1-methyl-2-(S)-pyrrolidinyl)methoxypyridine

(S)-1-Methyl-2-pyridinemethanol was reacted with triphenylphosphine,DEAD and 3-hydroxypyridine according to the procedure outlined inExample 1a. The crude product was purified by flash chromatography (2×)using (10%MeOH/CHCl₃) to remove the diethyl hydrazine dicarboxylateimpurity and give a yellow oil in 31% yield. MS (DCI/NH₃) m/e 193(M+H)⁺. ¹ H NMR (CDCl₃,300 MHz) δ: 8.32 (t, J=1.5 Hz, 1H), 8.22 (t, J=3Hz, 1H), 7.24-7.2 (m, 2H), 4.14-4.05 (dd, J=9, 6 Hz, 1if), 4.00-3.93(dd, J=9, 6 Hz, 1H), 3.24-3.14 (m, 1H), 2.81-2.7 (m, 1H), 2.54 (s, 3H),2.44-2.31 (m, 1i), 2.14-2.00 (m, 1H), 1.96-1.71 (m, 3H).

4b. 3-((1-methyl-2-(S)-pyrrolidinyl)methoxy pyridine fumarate

The compound of step 4a was dissolved in anhydrous MeOH and brought to0° C. with stirring. Fumaric acid was dissolved in MeOH with sonicationand added dropwise to the solution containing amine. The mixture waswarmed to room temperature with stirring. After 30 minutes the solventwas evaporated in vacuo and the remaining solid was vacuum filtered. Thesolid was then recrystallized with MeOH/Et₂ O to give the desiredproduct as a white powder (21% yield). m.p.=124-125° C. α!²⁵ D=-3.9°(c=1, MeOH). MS (DCI/NH₃) m/e 193 (M+H)⁺. ¹ H NMR (D₂ O,300 MHz) δ: 8.43(br s, 1H), 8.33 (d, J=4.5 Hz, 1H), 7.88-7.84 (m, 1H), 7.3 (dd, J=8.82,5.15 Hz, 1H), 6.58 (s, 2H), 4.59 (dd, J=l1, 3 Hz, 1H), 4.42 (dd, J=11,5.88 Hz, 1H), 4.05-3.9 (m, 1H), 3.82-3.74 (m, 1H), 3.34-3.22 (m, 1H),3.05 (s, 3H), 2.47-2.37 (m, 1H), 2.30-2.06 (m, 3H). Analysis calculatedfor C₁₁ H₁₆ N₂ OΩC₄ H₄ O₄ ; C, 58.43; H, 6.54; N, 9.09; Found: C, 58.32;H, 6.67; N, 8.99.

EXAMPLE 5

2-((1-methyl-2-(R)-pyrrolidinyl)methoxy-6-chloropyridazine oxalate

5a. 2-((1-methyl-2-(R)-pyrrolidinyl)methoxy-6-chloropyridazine

(R)-1-Methyl-2-pyrrolidinemethanol (300 mg, 2.61 mmol) was dissolved inanhydrous THF and cooled to 0° C. with stirring. NaH (80% dispersion inmineral oil, 0.082 g, 2.9 mmol) was added and the mixture was slowlywarmed to room temperature with stirring. After 30 minutes a THFsolution of 3,6-dichloropyridazine (0.41 g, 2.74 mmol) was added to themixture via syringe. The reaction was stirred for 48 hours. The solventwas then evaporated in vacuo and the mixture diluted with chloroform,washed with saturated NaHCO₃ and then with brine. The organic layer wasdried over MgSO₄. The resulting crude material was purified by flashchromatography (10% MeOH/CHCl₃) to give 0.25 g (42% yield) of the titlecompound as a cream colored solid.. MS (DCI/NH₃) m/e 228 (M+H)⁺. α!²⁵D=+320 (c=1, MeOH).

5b. 2-((1-methyl-2-(R)-pyrrolidinyl)methoxy)-6-chloropyridazine oxalate

The compound of step 5a was dissolved in anhydrous ether and cooled to0° C. with stirring. Oxalic acid, pre-dissolved in ether, was addeddropwise to the solution and mixture warmed to room temperature. After30 minutes of stirring, the solvent was removed in vacuo and theresulting solid was recrystallized with MeOH/Et₂ O to yield 0.28 g (82%of the title compound as a white powder. m.p.=153-154° C. MS (DCI/NH₃)m/e 228 (M+H)⁺. ¹ H NMR (D₂ O,300 MHz) δ: 7.76 (d, J=9 Hz, 1H), 7.36 (d,J=9 Hz, 1H), 4.83 (dd, J=12, 3 Hz, 1H), 4.66 (dd, J=12, 6 Hz, 1H),4.0-3.92 (m, 1H), 3.8-3.72 (m, 1H), 3.3-3.21 (m, 1H), 3.04 (s, 3H),2.46-2.37 (m, 1H), 2.28-2.02 (m, 3H). Analysis calculated for C₁₀ H₁₄ N₃OCl C₂ H₂ O₄ : C, 45.36; H, 5.08; N, 13.23; Found C, 45.46; H, 5.02, N,13.26.

EXAMPLE 6

3-(a-methyl-(1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine hydrochloride

6a. N-(carbobenzyloxy)-a-methyl-2-pyrrolidinemethanol

To a solution of N-carbobenzyloxy-pyrolinal (1.0 g, 4.28 mmol, see Moriet al., Tetrahedron, 1985, 41:5465) in Et₂ O (15 mL) at 0° C. was addedmethyl Grignard (1.4M in THF/toluene; 3.36 mL, 4.71 mmol), and two more1 mL aliquots of methyl Grignard were added at 5 minute intervals. Thereaction mixture was then diluted with Et₂ O (100 mL) and washed with 50mL portions of 5% aq. HCl (1×), and brine (1×), dried (MgSO₄), andconcentrated to afford the crude product as a clear oil (956 mg).Chromatographic purification (silica, EtOAc/Hex 1:2) afforded theproduct as a mixture of diastereomers (432 mg, 40% yield). ¹ H-NMR(CDCl₃) δ: 7.36 (m, 5H); 5.15 (s, 2H); 4.02 (br s, 1H); 3.86-3.39 (m,4H); 2.06-1.60 (m, 4H); 1.18, 1.11(two d, 3). MS(DCI/NH₃) m/e 250(M+H)⁺.

6b. a1-dimethyl-2-(S)-pyrrolidinemethanol

To a solution of the compound of step 6a (224 mg, 0.898 mmol) in Et₂ O(6 mL) was added LAH (50 mg, excess) and the reaction mixture refluxedfor 0.5 hours, then stirred at room temperature for 17 hours. Thereaction mixture was then quenched with Na₂ SO₄ decahydrate (500 mg)followed by EtOAc (6 mL), then filtered and the salts washed withethanol. The combined washes were combined and concentrated to affordthe crude product as a gel (138 mg). ¹ H-NMR (CDCl₃) δ: 3.87, 3.72,3.40, 3.05 (m, 2); 2.47, 2.32 (two s, 3); 2.44-2.33 (m, 1); 1.98-1.84(m, 1); 1.83-1.63, 1.55-1.45 (m, 4); 1.16, 1.12(two d, 3). MS(DCI/NH3)m/e 130 (M+H)⁺.

6e. 3-(a-methyl-(1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridinehydrochloride

To a solution of triphenylphosphine (353 mg, 1.34 mmol) in THF (4 mL) at0° C. was added DEAD (212 mL, 1.34mmol), and after3 minutes a solutionof the product of Example 6b (116 mg, 0.897 mmol) and 3-hydroxypyridine(94 mg, 0.98 mmol) in THF (5 mL) was added. The reaction mixture wasstirred at 0° C. for 6 hours then at room temperature for 15 hours. Thereaction mixture was then diluted with CH₂ Cl₂ (30 mL) and washed with10-mL portions of 10% aq. NaOH (2×) followed by 10% aq. HCl (3×). Thecombined acidic aqueous layers were basified is to pH 14 and extractedwith CH₂ Cl₂ (3×10 mL), the combined CH₂ Cl₂ washes dried (MgSO₄) andconcentrated to afford the crude product Treatment with 40% KOH (toremove DEAD by-product) followed by chromatographic purification(silica, EtOAc/EtOH/NH₄ OH 100:30:0.5) afforded the product as a mixtureof diastereomers, which was converted to the hydrochloride salt as awhite hygroscopic solid. (9 mg, 4% yield). ¹ H-NMR (D₂ O) δ: 8.58, 8.47,8.26, 8.04 (four m, 4), 5.07-4.89 (m, 1); 3.97-3.52 (m, 2); 3.34-3.14(m, 1); 3.09, 2.93 (two s, 3); 3.07-2.84 (m, 1); 2.53-1.78 (m, 4); 1.50,1.44 (two d, 3). MS(DCl/NH₃) m/e 207 (M+H)⁺.

EXAMPLE 7

2-(2-(S)-azetidinylmethoxy)pyrazine)dihydrochloride

7a. 1-t-butyloxycarbonyl-2-(S)-azetidinecarboxylic acid

To an ice cooled solution of 2-(S)-azetidinecarboxylic acid (10.15 g,100.39 mmol) in 1, 4 dioxane:water (300 mL, 1:1) was added di-tert-butyldicarbonate (28.48 g, 130.51 mmol), followed by 4methylmorpholine (11.68g, 115.45 mmol). The reaction mixture continued to stir 18 hours,gradually warming to room temperature. The reaction mixture was thenpoured into a ice cooled saturated solution of sodium bicarbonate (250mL) and washed with ethyl acetate (3×250 ml). The aqueous was thenacidified with potassium hydrogen sulfate (pH=1) and the productextracted with ethyl acetate (3×300 ml). These extracts were then dried(Na₂ SO₄), filtered and concentrated in vacuo. The resulting semisolidwas carried forward without further purification. MS (DCI/NH₃) m/e 202(M+H)⁺, 219 (M+NH₄)⁺. ¹ H NMR (CDCl₃,300 MHz) δ: 10.0 (br s, 1H),4.81-4.76 (t, J=15Hz, 1H), 3.99-3.83 (m, 2H), 2.62-2.38 (m, 2H), 1.48(s, 9H).

7b. 1-t-butyloxycarbonyl-2-(S)-azetidinemethanol

To an ice-cooled solution of the compound of step 7a (9.39 g, 46.72mmol) in tetrahydrofuran (100 mL) was added borane/THF complex (1 M, 210mL, 4.5 eq.) under nitrogen. The reaction was gradually warmed to roomtemperature and stirred for 48 hours, after which a 10% aqueouspotassium hydrogen sulfate solution (60 mL) was added gradually, thenthe volatiles were evaporated in vacuo, . The remaining slurry wasdiluted with ethyl acetate (100 mL), and triturated two additionaltimes. The organic phase was then washed with a saturated solution ofsodium hydrogen carbonate (3×75 mL), dried (MgSO₄), filtered andconcentrated in vacuo, yielding a colorless oil (8.4 g, 96% yield). Thismaterial was carried forward without further purification. MS (DCI/NH₃)m/e 188 (M+H)⁺. ¹ H NMR (CDCl₃,300 MHz) δ: 4.49-4.40 (ddd, J=9.0 Hz,J=9.0 Hz, J=3.0 Hz, 1H), 3.95-3.68 (m, 4H), 2.23-2.12 (m, 1H), 1.99-1.87(m, 111), 1.46 (s, 9H).

7c. 2-((1 4-butyloxycarbonyl-2-(S)-azetidinyl)methoxy)pyrazine

To an ice cooled solution of the compound of step 7b (941 mg, 5.0 mmol)in tetrahydrofuran (30 mL) under nitrogen, was added sodium hydride (80%dispersion in mineral oil, 180 mg, 7.5 mmol), portionwise. The reactionmixture stirred fifteen minutes followed by the dropwise addition of2-chloropyrazine (590 mg, 5.1 mmol). The reaction was stirred 24 hoursgradually warming to room temperature. Additional sodium hydride (40 mg)was added and stirring at room temperature continued until completedisappearance of starting material by TLC. The reaction mixture was thentreated with a 10%o aqueous solution of potassium hydrogen sulfate (20ml) and the volatiles evaporated in vacuo . The mixture was then dilutedwith ethyl acetate (50 ml) and the organic phase was washed withsaturated sodium hydrogen carbonate (2×20 ml). The organic phase wasthen dried (MgSO₄), filtered and concentrated in vacuo. The resultantorange oil (1.37 g) was purified by flash silica gel chromatography(ethyl acetate:hexane=1: 1), resulting in product isolated as an oil, in80% yield (1.07 g). α!_(D) ²³° =-62.8° (c 1.35, CHCl₃). MS(CI/NH₃) m/e266 (M+H)⁺, 283 (M+NH₄)⁺. ¹ H NMR (CDCl₃, 300 MHz) d 8.28-8.27 (d, J=1.1Hz, 1H), 8.13-8.12 (d, J=2.58Hz, 1H), 8.08-8.06 (dd, J=2.58, J=1.5Hz,1H), 4.66-4.61 (dd, J=10.83, J=4.6, 1H), 4.58-4.51 (m, 1H), 4.50-4.45(dd, J=10.83, J=3.13, 1H), 3.92-3.87 (dd, J=8.3, J=6.25, 2H), 2.41-2.29(m, 1H), 2.26-2.16 (m, 1H), 1.41 (s, 9H) .

7d. 2-(2-(S)-azetidinylmethoxy-2pyrazine dihydrochloride

The compound of step 7c (335 mg, 1.26 mmol) was stirred in methylenechloride (2 ml) and cooled to 0° C. To this was added trifluoroaceticacid in methylene chloride (3 ml, 1:1). The reaction was stirred 18hours, gradually warming to room temperature. The mixture was thenbasified (pH=9) with a saturated solution of sodium hydrogen carbonateand continuously extracted with methylene chloride for 16 hours. Theextract was dried (MgSO₄); filtered and concentrated in vacuo. Theresultant oil was not purified further, but was was dissolved in ethanol(2 mL) and immediately treated with diethyl ether saturated withhydrogen chloride gas. Crystals began to form immediately.Recrystallization from ethanol and diethyl ether yielded pure product(51.2 mg, 0.256 mmol, 80% yield) as the hydrochloride salt. mp (dec) MS(DCI/NH₃) m/e 166 (M+H)⁺, 183 (M+NH₄)⁺. ¹ H NMR (D₂ O, 300 MHz) δ: 8.37(s, 1H), 8.23 (s, 2H), 4.97-4.92 (m, 1H) 4.74-4.58 (m, 2H), 4.19-4.00(m, 21), 2.72-2.62 (dd, J=16.8 Hz, J=8.8 Hz, 2H). Anal. calcd. for C₈H₁₁ N₃ OΩ2.4 HCl: C, 38.02; H, 5.34; N, 16.63. Found: C, 37.99; H, 5.37;N, 16.60.

EXAMPLE 8

2-((1-methyl-2-(S)-azetidinyl)methoxy)pyrazine dihydrochloride

The compound of Example 7a (102.9 mg, 0.62 mmol) was stirred with excessparaformaldehyde in ethanol (5 mL), on ice and under nitrogen, and thepH adjusted to five with the addition of acetic acid and sodium acetate.The reaction was stirred for 15 minutes and sodium cyanoborohydride (59mg, 0.936 mmol) was added. A very small amount of bromocresol green wasadded directly to the reaction mixture as indicator. The reaction wasstirred 18 hours, allowed to warm to room temperature, and additionalformaldehyde (0.25 mL) and sodium cyanoborohydride (20 mg, 0.32 mmol)was added to push the reaction to completion. The reaction mixture wasthen acidified (pH=1) with 10% solution of potassium hydrogen sulfateand the volatiles evaporated. The aqueous phase was washed with ethylacetate (3×10 mL), basified with sodium carbonate (pH=9.5), and productsextracted with ethyl acetate (5×15 mL). These extracts were dried(MgSO₄), filtered, and concentrated in vacuo. The resultant oil (111.7mg, 100% yield), was then purified by flash silica gel chromatography(chloroform:methanol:ammonium hydroxide/98:2:0.1), yielding the pureproduct (60.1 mg, 54% yield), which was dissolved in ethanol andconverted to the hydrochloride salt in a similar manner as that ofExample 7d, (62.2 mg, 86% yield). mp 161-162° C. (dec). MS (DCI/NH₃) m/e180 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) b: 8.37 (S, 1H), 8.24 (s, 21J),4.87-4.76 (m, 1H), 4.32-4.23 (ddd, J=10 Hz, J=10 Hz, J=6 Hz, 1H),4.04-3.95 (dd, J=19.5 Hz, J=9.6 Hz, 1H), 2.97 (s, 3H), 2.70-2.58 (m,2H). Anal. calcd. for C₉ H₁₃ N₃ OΩ2.0 HClΩ0.3 H₂ O: C, 41.97; H, 6.10;N, 16.32. Found: C, 42.25; H, 5.93; N, 16.02.

EXAMPLE 9

3-(2-(S)-azetidinylmethoxy)pyridine dihydrochloride

9a. 3-((1-t-butyloxycarbonyl-2-(S)-azetidinyl)methoxy)pyradine

An ice cooled solution of the compound of Example 7b (2.8 g, 14.97 mmol)in tetrahydrofuran (40 mL) was stirred under a nitrogen atmosphere Tothis was is added DEAD (3.54 mL, 22.46 mmol) followed bytriphenylphosphine (4.78 g, 22.46 mmol) and the mixture was stirred 10minutes. 3-Hydroxypyridine (2.14 g, 22.46 mmol) was then added to thereaction with additional tetrahydrofuran (40 mL). After 18 hours,additional 3-hydroxypyridine (0.1 g, 1.05 mmol) was added and thereaction stirred 24 hours longer. When all starting azetidine alcoholwas consumed, the reaction mixture was concentrated in vacuo. The crudemixture was then acidified (pH<2) with a 10% solution of potassiumhydrogen sulfate (80 mL), and washed with ethyl acetate (3×75 mL). Theaqueous portion was then basified with a saturated solution of potassiumcarbonate (pH=10) and products extracted with ethyl acetate (4×75 mL).These extracts were dried (MgSO₄), filtered and concentrated in vacuo toa red-brown oil (1.84 g, 50% yield). The crude product was purified viaflash silica gel chromatography R_(f) =0.19, (ethyl acetate:hexane=2:1),yielding product as a light yellow oil in 25% yield. MS (DCI/NH₃) m/e265 (M+H)⁺, 282 (M+NH₄)⁺. ¹ H NMR (CDCl₃) 8:83-8.35 (dd, J=3.7 Hz, J=0.7Hz, 1H), 8.24-8.22 (dd, J=4.0 Hz, J=1.5 Hz, 1H), 7.25-7.22 (m, 2H),4.56-4.48 (m, 1H), 4.36-4.31 (dd, J=10 Hz, J=4.9 Hz, 1H), 4.17-4.12 (dd,J=10 Hz, J=2.9 Hz, 1H), 3.92-3.87 (dd, J=8.2 Hz, J=6.8 Hz, 2H),2.42-2.25 (m, 2H), 1.42 (s, 9H).

9b. 3-(2-(S)-azetidinylmethoxypyridine dihydrochloride

To an ice cooled solution of the compound of step 9a (286 mg, 1.08 mmol)in absolute ethanol (4 mL), was added a hydrogen chloride saturatedethanol solution (4 mL), under nitrogen. The reaction mixture wasstirred 18 hours while gradually warming to room temperature. Thereaction mixture was then concentrated in vacuo, the product dissolvedin absolute ethanol and triturated with diethyl ether. Tworecrystallizations from ethanol and diethyl ether yielded pure productin 81% yield as a white powder (174 mg, 87 mmol). MS (DCI/NH₃) m/e 165(M+H)⁺, 182 (M+NH₄)⁺. ¹ NMR (D₂ O,300 MHz) δ: 8.60-8.59 (d, J=2.9 Hz,1H), 8.48-8.46 (d, J=5.8 Hz, 1H), 8.25-8.21 (ddd, J=9.0 Hz, J=2.6 Hz,J=1.1 Hz, 1H), 5.05-4.97 (m, 1H), 4.59-4.57 (d, J=4.0 Hz, 2H), 4.22-4.05(m, 2H), 2.77-2.67 (dd, J=16.9 Hz, J=8.45 Hz, 2H). Anal. calcd. for C₉H₁₂ N₂ OΩ2.7 HClΩ0.2 H₂ O: C, 40.60; H, 5.71; N, 10.52. Found: C, 40.75;H, 5.76; N, 10.51.

EXAMPLE 10

3-((1-methyl-2-(S)-azetidinyl)methoxy pyridine dihydrochloride

To an ice cooled solution of the compound of Example 9a (550 mg, 1.89mmol) in methylene chloride (3 ml) under nitrogen, was addedtrifluoroacetic acid in methylene chloride (5 ml, 1:1). The reaction wasstirred 18 hours, gradually warming to room temperature. The reactionmixture was then concentrated in vacuo, brought up in absolute ethanol(5 ml). Paraformaldehyde was added, and the acidity adjusted to pH 5with the addition of acetic acid and sodium acetate. The reactionmixture was stirred for 15 minutes and sodium cyanoborohydride (180 mg,2.86 mmol) was added. A small amount of bromocresol green was added tothe reaction mixture as indicator. The mixture stirred 18 hours afterwhich time the reaction was complete as monitored by TLC. The reactionmixture was then acidified (pH=1) with saturated solution of potassiumhydrogen sulfate, and the volatiles evaporated in vacuo. The aqueousphase was then washed with ethyl acetate (3×20 ml), basified (pH=10)with potassium carbonate, and the crude products extracted with ethylacetate (4×20 ml). The extracts were dried (MgSO₄), filtered andconcentrated in vacuo (274 mg, 81% yield). The crude product was thenpurified by flash silica gel chromatography, yielding a colorless oil(147 mg, 44% yield). This oil was dissolved in absolute ethanol (1.5 mL)and treated with hydrogen chloride saturated diethyl ether. After onerecrystallization from ethanol and diethyl ether, pure product resultedin the form of fine hygroscopic needles. MS (CI/NH₃) m/e 179 (M+H)⁺, 196(M+NH₄)⁺. ¹ H NMR (D₂ O/300 MHz) d 8.53 (d, J=2.2Hz, 1H), 8.42-8.41 (d,J=5.5 Hz, 1H), 8.09-8.05 (dd, J=8.8 Hz, J=3.0 Hz, 1H), 7.91-7.86 (dd,J=8.8 Hz, J=5.4 Hz, 1H), 4.90-4.80 (m, 1H), 4.63-4.58 (dd, J=11.8 Hz,J=2.9 Hz, 1H), 4.56-4.50 (dd, J=11.8 Hz, J=5.3 Hz, 1H), 4.34-4.25 (ddd,J=9.9 Hz, J=9.9 Hz, J=5.1, 1H), 4.06-3.97 (dd, J=19.5 Hz, J=9.4 Hz, 1H),3.00 (s, 3H), 2.77-2.60 (m, 2H). Anal. calc. for C₁₀ H₁₄ N₂ OΩ2.0HClΩ0.7 H₂ O: C, 45.54; H, 6.65; N, 10.62. Found: C, 45.38; H, 6.35; N,10.53.

EXAMPLE 11

2-((1-methyl-2-(S)-pyrrolidinyl)methoxythiazole hydrochloride

(S)-(-)-1-Methyl-2-pyrrolidine methanol (484 mg, 4.2 mmol) was reactedwith NaH ((80% dispersion in mineral oil) 0.164 g 5.46 mmol) and2-bromothiazole (0.417 g, 4.62 mmol) according to the procedure outlinedin Example 3a to afford after column chromatography eluting with (10%MeOH/CHCl₃ +1% NH₃) (616.2 mg, 3.1 mmol, 74% yield) of2-(1-methyl-2-(S)-pyrrolidinylmethoxy)-thiazole. The pure base was thenconverted to its hydrochloride salt by treating the amine (109.4 mg,0.552 mmol) with a saturated solution of HCl in Et₂ O dropwise withstirring until no more precipitate formation was observed. This afforded21.2 mg, 0.09 mmol, 16% of the title compound. mp=99°C. α!D²⁰ =+2.86°(c=0.021, MeOH). MS (DCI/NH₃) m/e 199 (M+H)⁺. ¹ H NMR (CD30D, 300 Mz) δ:7.18 (d, J=4.04 Hz, 1H), 6.99 (d, J=4.04 Hz, 1H), 4.85 (dd, J=12.50,3.31 Hz, 1H), 4.65 (dd, J=12.5, 6.62 Hz, 1H), 4.09-3.85 (m, 1H),3.85-3.65 (m, 1H), 3.03 (br s, 3H), 2.45-2.3 (m, 1H), 2.3-1.95 (m, 3H).Analysis calculated for C₉ H₁₅ N₂ OSClΩ0.6 H₂ OΩ0.1Et₂ O: C, 44.63; H,6.85; N, 11.07; Found: C, 44.68; H, 6.46; N, 10.68.

EXAMPLE 12

3-((1-methyl-2-(S)-pyrrolidinyl)methoxy-6-chloropyridazine fumarate

12a. 3-((1-methyl-2-(S)-pyrrolidinyl)methoxy -6-chloropyridazine

(S)-(-)-1-Methyl-2-pyrrolidinemethanol (968 mg, 8.4 mmol) was reacted ina similar fashion as that described for the (R)-isomer of Example 5a toafford 1.31 g (69% yield) of the title compound. α!²⁵ =-28.3° (c=1.1,MeOH).

12b. 3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)-6-chloropyridazinefumarate

The compound of step 12a (37.3 mg, 0.16 mmol) was reacted with 19 mg offumaric acid in a process similar to that described in Example 4b toafford 39 mg (70% yield) of the title compound as a white solid,m.p.=155° C. α!²⁰ =+4.80° (c=1.0, MeOH). MS (DCI/NH₃) m/e 228 (M+H)⁺. ¹H NMR (D₂ O, 300 MHz) δ: 7.6 (d, J=9.19 Hz, 1H), 7.37 (d, J=9.19 Hz,1H), 6.64 (s, 2H), 4.82 (dd, J=12.14, 3.1 Hz, 1H), 4.66 (dd, J=12.13,5.88 Hz, 1H), 4.0-3.92 (m, 1H), 3.8-3.72 (m, 1H), 3.3-3.21 (m, 1H), 3.04(s, 3H), 2.46-2.36 (m, 1H), 2.27-2.02 (m, 3H). Analysis calculated forC₁₄ H₁₈ N₃ O₅ Cl: C, 48.91; H, 5.27; N, 12.22; Found: C, 48.86; H, 4.87;N, 11.98.

EXAMPLE 13

6-chloro-3-((1-methyl-2(S)-azetidinyl)methoxy)pyridazine oxalate

13a. 3-((1-BOC-2(S)-azetidinyl)methoxy-6-chloro-pyridazine

The compound from Example 7b (3.18 g, 17.0 mmol), sodium hydride (80%dispersion in mineral-oil, 510 mg, 17.0 mmol), and3,6-dichloropyridazine (3.8 g, 25.5 mmol) were combined in a similarmanner as that described in Example 7c. The crude product was purifiedby flash chromatography on silica gel using EtOAc/hexane (1:6 to 1:4) asthe elutant to give 3.87 g of a viscous oil, which solidified in therefrigerator (76% yield). TLC R_(f) =0.58 (EtOAc/hexane 1:1). mp. 50-54°C. MS (CI) m/e 300 (M+H)⁺. ¹ H NMR (DMSO-d₆, 300 MHz) 5: 7.73 (d, J=9.2Hz, 1H), 7.31 (d, J=9.2 Hz, 1H), 4.72 (dd, J=11.0 Hz, 4.6 Hz, 1H), 4.59(dd, J=11.0 Hz, 3.7 Hz, 1H), 4.56-4.50 (m, 1H), 3.79 (t, J=7.6 Hz, 2H),2.40-2.38 (m, 1H), 2.20-2.09 (m, 1H), 1.36 (s, 9H).

13b. 6-chloro-3-((1-methyl-2(S)-azetidinylmethoxy pyridazine

The compound from step 13a (805 mg, 2.68 mmol) was treated in a similarfashion as that described under Example 7d. The crude was subject toflash chromatography on silica gel with 10% MeOH in CHCl₃ to 0.5% NH₄ OHin 10% MeOH in CHCl₃ used as the elutant to give 352 mg of a yellow oil(66% yield). MS (CI) m/e 200 (M+H)⁺. The amine deprotected material (330mg, 1.66 mmol) was then subjected to reductive-amination conditionspreviously described in Example 8. The crude product was purified byflash chromatography on silica gel using 2% MeOH in CHCl₃ to 5% MeOH inCHCl₃ as the elutant to give 125 mg of a clear oil (35% yield). MS (CI)m/e 214 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) d 7.36 (d, J=9.2 Hz, 1H), 7.02(d, J=9.2 Hz, 1H), 4.54 (dd, J=11.6 Hz, 3.8 Hz, 1H), 4.47 (dd, J=11.6Hz,5.7 Hz, 1H), 3.48-3.39 (m, 2H), 2.89-2.81 (m, 1H), 2.38 (s, 3H),2.17-2.03 (m, 2H).

13c. 6-chloro-3-((1-methyl-2(S)-azetidinyl)methoxy)pyridazine oxalate

The compound of step 13b (120 mg, 0.56 mmol) was dissolved in 8 mL ofdiethyl ether and cooled to 020 C. Oxalic acid (55.5 mg, 0.62 mmol) in 1mL of diethyl ether was added dropwise to the reaction vessel, and thereaction was stirred for 30 minutes. The solvent was then removed invacuo and the remaining white solid recrystallized out of hot methanolto give 128 mg of the title compound (75% yield). mp=165-167° C. α!D²³=-26.7° (c 0.75, H₂ O). MS (CI) m/e 214 (M+H)⁺. ¹ H NMR (D₂ O,300 MHz)δ: 7.78 (d, J=9.2 Hz, 1H), 7.40 (d, J=9.2 Hz, 1H), 4.89-4.73 (m, 3H),4.32-4.22 (m, 1H), 4.05-3.94 (m, 1H), 297(s, 3H), 2.73-2.60 (m, 2H).Anal Calc for C₁₁ H₁₄ ClN₃ O₅ : C, 43.50; H, 4.65; N, 13.84. Found: C,43.59; H, 4.50; N, 13.65.

EXAMPLE 14

3-(2-(S)-pyrrolidinylmethoxypyridine fumarate

14a 3-((1-t-butoxycarbonal-2-(S)-pyrrolidinyl)methoxy pyridine

To a solution of triphenylphosphine (1.97 g, 7.5 mmol) in 30 mL oftetrahydrofuran at room temperature was added diethyl azodicarboxylate(DEAD) (1.13 mL, 7.5 mmol) dropwise with stirring. After stirring atroom temperature for 30 minutes,(S)-1-t-butoxycarbonyl-2-pyrrolidinemethanol (from Example 15a below, 1g, 5.0 mmol) and 3-hydroxypyridine (713 mg, 7.5 mmol) were added to thereaction mixture. The resultant solution was stirred at room temperaturefor 16 hr. After all the starting material was consumed, the organicsolvent was evaporated in vacuo. The residue was purified by silica gelcolumn chromatography. Elution with chloroform:methanol (10:1) provided2 g of the title compound MS (DCI/NH₃) m/e 279 (M+H)⁺.

14b. 3-(2-(S)-pyrrolidinylmethoxy)pyridine

To a solution of the compound of step 14a in 12 mL of methylene chloridesolution was added 12 mL of trifluoroacetic acid. The resultant solutionwas stirred at room temperature for 3 hr. Evaporation of both solventand trifluoroacetic acid gave a brown oil which was basified withsaturated ammonium hydroxide solution. This oil was purified by silicagel column chromatography. Elution with a mixture ofchloroform:methanol: ammonium hydroxide (10:1:0.1) provided the desiredproduct. MS (DCI/NH₃) m/e 179 (M+H)⁺. ¹ H NMR (D₂ O,300 MHz) δ; 8.33 (brs, 1H), 8.22 (m, 1H), 7.22(m, 2H), 3.82-4.03 (m, 2H), 3.50-3.61 (m, 1H),2.92-3.10(m, 2H), 1.70-2.10 (m, 4H), 1.51-1.66 (m, 1H).

14c. 3-(2-(R)-pyrrolidinylmethoxy)pyridine fumarate

The compound of step 14b (281 mg, 1.57 mmol) was dissolved in anhydrousMeOH and brought to 0° C. with stirring. Fumaric acid was dissolved inMeOH with sonication and added dropwise to the base. The mixture waswarmed to room temperature with stirring. After 30 minutes the solventwas evaporated in vacuo, and the remaining solid was triturated withanhydrous diethyl ether. The product was obtained as a hygroscopic solidin 47% yield (218 mg). MS (DCI/NH₃) m/e: 179 (M+H)⁺. ¹ H NMR (D₂ O,300MHz) δ: 8.38 (m, 1H), 8.30 (m 1H), 7.76-7.72 (m, 1H), 7.72-7.62 (m, 1H),6.57 (s, 2H), 4.60-4.50 (m, 1H), 4.35-4.25 (m, 1H), 4.10-4.08 (m, 1H),3.42 (t, J=7.5 Hz, 2H), 2.37-2.23 (m, 1H), 2.23-2.06 (m, 2H), 2.06-1.98(m, 1H). Anal calc. for C₁₀ H₁₄ N₂ OΩC₂ H₄ O₂ Ω0.9 H₂ O: C, 54.15; H,6.42; N, 9.02; Found: C, 54.48; H 6.02; N, 8.67.

EXAMPLE 15

5-chloro-3-(2-(S)-pyrrodinylmethoxypyridine dihydrochloride

15a. (S)-1-t-Butoxycarbonyl-2-pyrrolidinemethanol

N-t-BOC-proline (Sigma Chemical Co., 12.97 g, 60.02 mmol) was dissolvedin anhydrous THF and brought to 0° C. with stirring. Borane/THF complexwas added dropwise via syringe over a 10 minute period. The reactionmixture was stirred at room temperature for 1 hour, then the reactionwas quenched slowly with saturated NaHCO₃ and stirred for an additionalhour. The solvent was removed in vacuo, and the residue was diluted withH₂ O. The desired compound was extracted from the aqueous phase with Et₂O (3×). The organic layer was then washed with brine (2×) dried (MgSO₄)and evaporated. The resulting material was carried on without furtherpurification.

15b. 5-chloro-3-((1-t-butoxycarbonyl-2-(S)-pyrrolidinyl)methoxy)pyridine

(S)-1-t-Butoxycarbonyl-2-pyrrolidinemethanol (1.75 g, 8.71 mmol,prepared as in Example 11a) and 5-chloro-3-pyridinol (1.69 g, 13.10mmol, Aldrich Chemical Co.). were allowed to react in the presence oftriphenylphosphine and DEAD as described in Example 2a. The crudeproduct was purified by chromatography over silica gel eluted withhexane/EtOAc to provide 1.49 g (60%) of the title compound as a paleyellow oil. TLC R_(f) 0.75 (1:1 EtOAc/Hex). MS (DCI/NH₃) m/e 313 (M+H)⁺with 35CI and m/e 315 (M+H)⁺ with ³⁷ Cl.

15c. 5-chloro-3-(2-(S)-pyrrolidinylmethoxypyridine

The compound of step 15b (0.440 g, 1.41 mmol) was treated withtrifluoroacetic acid in CH₂ Cl₂ as described in Example 2b, thensaturated K₂ CO₃ was added and the aqueous phase was extracted with CH₂Cl₂ (3×). The organic layer was dried (MgSO₄) and evaporated, and thecrude product was purified by chromatography over silica gel eluted withCHCl_(3/) MN H/NOH/to give 0.299 g (100%) of the title compound as apale yellow oil. MS (DCI/NH₃) m/e: 213 (M+H)⁺ with ³⁵ Cl and 215 (M+H)⁺with ³⁷ Cl. ¹ H NMR (CDCl₃, 300 MHz) δ:8.22 (d, J=2.6 Hz, 2H), 8.19 (d,J=2.2 Hz, 1H), 7.22 (t, J=2.50 Hz, 1H), 3.97 (dd, J=9, 5 Hz, 1H), 3.90(dd, J=9,7 Hz, 1H), 3.60-3.51 (m, 1H), 3.08-2.95 (m, 2H), 2.32 (br s,1H), 2.03-1.74 (m, 3H), 1.62-1.51 (m, 1H). α!D²⁵ =+13.94° (c=1.04,MeOH).

15d. 5-chloro-3-(2-(S)-pyrrolidinylmethoxy pyridine dihydrochloride

The compound of step 15c was treated with HCl and isolated as describedin Example 1b to afford a cream colored powder. mp 183-186° C. MS(DCI/NH₃) m/e: 213 (M+H)⁺ with ³⁵ Cl and 215 (M+H)⁺ with 3⁷ Cl. ¹ H NMR(D₂ O, 300 MHz) δ: 8.23 (m, 2H), 7.60 (t, J=2.20 Hz, 1H), 4.47 (dd,J=10.60, 3.70 Hz, 1H), 4.25 (dd, J=10.60, 8 Hz, 1H), 4.14-4.10 (m, 1H),3.44-3.39 (t, J=7 Hz, 2H), 2.32-2.23 (m, 1H), 2.19-2.07 (m, 2H),2.01-1.92 (m, 1H). Anal. Calc. for C₁₀ H₁₃ N₂ OClΩ₂.00 HCl: C, 42.06; H,5.29; N, 9.81; Found C, 42.47; H, 5.34; N, 9.90. Ε!_(D) ²⁵ =+10.10°(c=1,MeOH).

EXAMPLE 16

5chloro-3-((1-methyl-2-(S)-pyrrolidinyl)methoxypyridine dihydrochloride

16a. 5- chloro-3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine

To 5-chloro-3-((1-t-butoxycarbonyl-2-(S)-pyrrolidinyl)methoxy)pyridine(0.600 g, 1.92 mmol), from Example 15b, was added a solution of formicacid/formaldehyde (1:2,3 mL). The mixture was heated at reflux for 3hours, then basified with sat. K₂ CO₃. The aqueous phase was extractedwith CH₂ Cl₂ (3×) then the organic layer was dried (MgSO₄) andconcentrated. The crude product was purified by chromatography oversilica gel eluted with CHCl_(3/) MeOH to afford 0.274 g (63%) of thetitle compound as a pale yellow oil. TLC R_(f) =0.23 (10%MeOH/CHCl₃). MS(DCI/NH₃) m/e: 227 (M+H)⁺ with 35Cl and 229 (M+H)⁺ with ³⁷ Cl. ¹ H NMR(CDCl₃, 300 MHz) δ: 8.22 (d, J=2.6 Hz, 1H), 8.19 (d, J=2.2 Hz, 1H), 7.22(t, J=2 Hz, 1H), 4.00 (dd, J=9, 5.50 Hz, 1H), 3.92 (dd, J=9, 5.20 Hz,1H), 3.14-3.08 (m, 1H), 2.69-2.64 (m, 1H), 2.47 (s, 3H), 2.36-2.27 (m,1H), 2.07-1.97 (m, 1H), 1.88-1.69 (m, 3H).

16b. 5chloro-3-(1-methyl-(S)-pyrrolidinylmethoxypyridine dihydrochloride

The compound of step 16a was treated with HCl and isolated as describedin Example 1b to give a white powder. mp=200° C. (dec). MS (DCI/NH₃)m/e: 227 (M+H)⁺ with 35Cl and 229 (M+H)⁺ with ³⁷ Cl. ¹ H NMR (D₂ O, 300Hz) δ: 8.25-8.24 (m, 2H), 7.63-7.61 (m, 1H), 7.62 (t, J=2.3 Hz), 4.53(dd, J=11, 3 Hz, 1H 4.36 (dd, J=9, 6 Hz, 1H), 3.94 (m, 1H), 3.76 (m,1H), 3.17-3.10 (m, 1H), 3.04 (s, 3H), 2.44-2.35 (m, 1H), 2.25-2.02 (m,3H). Anal. Calc. for C₁₁ H₁₅ N₂ OClΩ2.00 HCl: C, 44.10; H, 5.72; N,9.35; Found C, 44.07; H, 5.69; N, 9.35. α!_(D) ²⁵ =-5.60° (c=1, MeOH).

EXAMPLE 17

2-methyl-3-(2-(S)-pyrrolidinylmethoxy pyridine dihydrochloride 17a.2-methyl-3-((1-t-butoxycarbonyl-2-(S)-pyrrolidinyl)methoxy)pyridine

To a solution of triphenylphosphine (3.83 g, 14.6 mmol) in 40 mL ofanhydrous THF at 0° C. was added diethyl azodicarboxylate (2.30 mL, 14.6mmol) dropwise. The mixture was stirred at 0° C. for 30 minutes, thenbrought to room temperature.(S)-1-t-Butoxycarbonyl-2-pyrrolidinemethanol (1.96 g, 9.75 mmol, AldrichChemical Co.) and 2-methyl-3-hydroxypyridine (Aldrich Chemical Co., 1.60g, 14.6 mmol) were added to the reaction vessel, and the mixture wasstirred for 16 hours. Solvent was removed in vacuo, and the residue wasdiluted with hexane and sonicated for 30 minutes. The resultingprecipitate was filtered and washed with hexane. The hexane was removedin vacuo. The residue was purified by silica gel flash chromatography(ethyl acetate) to give 1.42 g (50% yield) of the title compound as apale yellow oil. TLC R_(f) =0.50 (EtOAc). MS (DCI/NH₃) m/e: 293 (M+H)⁺.

17b.. 2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine

To a solution of the compound of step 17a (0.407 g, 1.39 mmol) in 2 mLof methylene chloride at 0° C. was added 2 mL of trifluoroacetic acid.The reaction was stirred at this temperature for 40 minutes. Thetemperature was raised to room temperature, and the reaction was stirredfor an additional 30 minutes. Once the starting material was consumed,saturated K₂ CO3 was added and the product was extracted from theaqueous phase with CH₂ Cl₂ (3×). The organic layer was then dried overMgSO₄ The resulting crude material was purified by silica gel flashchromatography using a gradient from 100% CHCl₃ to 10% MeOH/CHCl₃ andfinally 1%NH₄ OH/10%MeOH(CHCl₃ to give 0.236 g (88%) of the titlecompound as a pale yellow oil. MS (DCI/NH₃) m/e: 193 (M+H)⁺. ¹ H NMR(CDCl₃, 300 MHz) δ: 8.07 (t, J=3 Hz, 1H), 7.07 (m, 2H), 3.95-3.85 (m,2H), 3.60-3.55 (m, 1H), 3.10-2.97 (m, 2H), 2.48 (s, 3H), 2.23 (br s,1H), 2.04-1.93 (m, 1H), 1.90-1.78 (m, 2H), 1.67-1.58 (m, 1H).

17c. 2-methyl-3-(2-(S)-pyrrolidinylmethoxypyridine dihydrochloride

The free base from step 17b was dissolved in diethyl ether and broughtto 0° C. with stirring. The solution was treated with diethyl ethersaturated with hydrogen chloride gas. The solvent was removed in vacuo.The resulting salt was triturated with diethyl ether (2X) and driedunder vacuum to give a beige-powder. mp.>240° C., and decompositionoccurs at 250° C. and higher. MS (DCI/NH₃) m/e: 193 (M+H)⁺. ¹ H NMR (D₂O, 300 Mz) δ: 8.17 (d, J=5.5 Hz, 1H), 7.86 (d, J=7.5 Hz, 1H), 7.67 (dd,J=8.50, 5.50 Hz, 1H), 4.58 (dd, J=11, 3 Hz,1H), 4.34 (dd, J=11, 8 Hz,1H), 4.25-4.19 (m, 1H), 3.46-3.42 (m, 2H), 2.62 (s, 3H), 2.36-2.28 (m,1H), 2.22-196 (m, 3H). Anal. Calc. for C₁₁ H₁₆ N₂ OΩ2.00 HCl: C, 48.82;H, 6.84; N, 10.56; Found C, 49.60; H, 6.88; N, 10.44. α!_(D) ²⁵ =+21.40°(c=1, MeOH).

EXAMPLE 18

6-methyl-3-(2-(S)-pyrrolidinylmethoxy pyridine dihydrochloride

18.a. 6-methyl-3-((1-t-butoxycarbonyl-2-(S)-pyrrolidinyl)methoxy)pyridine

To a solution of triphenylphosphine (3.83 g, 14.60 mmol) in 40 mL ofanhydrous THF at 0° C. was added diethyl azodicarboxylate (2.3 mL, 14.60mmol) dropwise. The mixture was stirred at 0° C. for 30 minutes, thenbrought to room temperature.(S)-1-t-Butoxycarbonyl-2-pyrrolidinemethanol (1.96 g, 9.75 mmol, AldrichChemical Co.) and 6-methyl-3-pyridinol (Aldrich Chemical Co.,1.60 g,14.60 mmol) were added to the reaction vessel, and the mixture wasstirred for 16 hours. Solvent was removed in vacuo, and the residue wasdiluted with hexane and sonicated for 30 minutes. The resultingprecipitate was filtered and washed with hexane. The hexane was removedin vacuo. The residue was purified by silica gel flash chromatographyusing a gradient from 100% hexane to a 1:1 solution of ethylacetate/hexane (100% Hex, 10%EtOAc/Hex, 20%EtOAc/Hex, 1:1 EtOAc/Hex) togive 1.61 g (57%) of the title compound as a pale yellow oil. TLCRf=0.42 (1:1 EtOAc/Hex). MS (DCI/NH₃) m/e: 293 (M+H)⁺.

18b. 6-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine

To a solution of the compound of step 18a above (0.320 g, 1.09 mmol) in2 mL of methylene chloride at 0° C. was added 2 mL of trifluoroaceticacid. The reaction was stirred at this temperature for 30 minutes. Thetemperature was raised to room temperature, and the reaction was stirredfor an additional 30 minutes. Once the starting material was consumed,saturated K₂ CO₃ was added, and the product was extracted from theaqueous phase with CH₂ Cl₂ (3×). The organic layer was then dried overMgSO₄. The resulting crude material was purified by silica gel flashchromatography using a gradient from 100% CHCl₃ to 10% MeOH/CHCl₃ andfinally 1% NH₄₀ H/10%MeOH/CHCl₃ to give 0.200 g (95%) of the titlecompound as a pale yellow oil. MS (DCI/NH₃) m/e: 193 (M+H)⁺. ¹ H NMR(CDCl₃, 300 Mz) δ: 8.20 (d, J=3 Hz, 1H), 7.12 (dd, J=8.50, 3 Hz, 1H),7.05 (d, J=8.50 Hz, 1H), 3.94 (dd, J=9, 5 Hz, 1H), 3.87 (dd, J=9, 7 Hz,1H), 3.57-3.48 (m, 1H), 3.07-2.92 (m, 2H), 2.48 (s, 3H), 2.18 (br s,1H), 2.01-1.89 (m, 1H), 1.88-1.71 (m, 2H), 1.62-1.51 (m, 1H). α!_(D) ²⁵=+11.40° (c=1, MeOH).

18c. 6-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

The free base from step 18b was dissolved in diethyl ether and broughtto 0° C. with stirring. The solution was treated with diethyl ethersaturated with hydrogen chloride gas. The solvent was removed in vacuo.The resulting salt was triturated with diethyl ether (2×) and driedunder vacuum to give a beige powder. mp.>100° C. (dec). MS (DCI/NH₃)m/e: 193 (M+H)⁺. ¹ H NMR (D₂ O,300 MHz) δ: 8.27 (d, J=3 Hz, 1H), 7.81(dd, J=9,3 Hz, 1H), 7.59 (d, J=9 Hz, 1H), 4.51 (dd, 10.50, 3.50 Hz, 1H),431 (dd, 10.50, 7.50 Hz, 1H), 4.19-4.12 (m, 1H), 3.43 (d, J=7 Hz, 2H),2.60 (s, 3H), 2.33-2.24 (m, 1H), 2.20-1.92 (m, 3H). Anal. Calc. for C₁₁H₁₆ N₂ OΩ2.00ΩHCl: C, 49.82; H, 6.84; N, 10.56; Found C, 49.78; H, 6.53;N, 10.26. α!_(D) ²⁵ =+10.00° (c=1, MeOH).

EXAMPLE 19

6methyl-3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine dihydrochloride

19a. 6methyl-3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine

To 3 mL of a solution of formic acid/formaldehyde (1:2) was added thecompound from Example 19a (0.600 g, 2.05 mmol). The mixture was broughtto a gentle reflux and stirred at this temperature (80° C.) for 3 hours.The reaction was basified with sat. K₂ CO₃. The desired compound wasextracted from the aqueous phase with CH₂ Cl₂ (3×). The organic layerwas dried over MgSO₄. The resulting crude material was purified bysilica gel flash chromatography using a gradient from 100% chloroform to10% methanol/chloroform (5% increments) to give 0.403 g (95%) of thetitle compound as a clear colorless oil. TLC Rf=0. 17 (10% MeOH/CHCl3).MS (DCI/NH3) m/e 207 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ: 8.21 (d, J=3Hz, 1H), 7.13 (dd, J=8.50, 3 Hz, 1H), 7.05 (d, J=8.50 Hz, 1H), 4.06 (dd,J=9, 5.50 Hz, 1H), 3.93 (dd, J=9, 5.50 Hz, 1H), 3.19-3.14 (m, 1H),2.74-2.69 (m, 1H), 2.52 (s, 3H), 2.48 (s, 3H), 2.37-2.31 (m, 1H),2.08-1.99 (m, 1H), 1.89-1.74 (m, 3H).

19b. 6-methyl-3-((1-methyl-2-(S)-pyrrolidinyl)methoxypyridinedihydrochloride

The free base from step 19a was dissolved in diethyl ether and broughtto 0° C. with stirring. This solution was treated with diethyl ethersaturated with hydrogen chloride gas. The solvent was removed in vacuo .The resulting salt was triturated with diethyl ether (2×) and driedunder vacuum to give a white powder. m.p.=213-216° C. MS (DCI/NH₃) m/e:207 (M+H)⁺. ¹ H NMR (D₂ O,300 MHz) δ: 8.28 (d, J=3 Hz, 1H), 7.79 (dd,J=9, 3 Hz, 1H), 7.58 (d, J=9 Hz, 1H), 4.56 (dd, J=11, 3 Hz, 1H), 4.39(dd, J=11, 6 Hz, 1H), 3.95 (br s, 1H), 3.77 (br s, 1H4), 3.28 (br s,I1H), 3.04 (s, 3H), 2.59 (s, 3H), 2.42-2.37 (m, IF), 2.25-2.08 (m, 3H).Anal. Calc. for C₁₂ H₁₈ N₂ OΩ2.00 HCl: C 51.62; H, 7.22; N. 10.03; FoundC, 51.49; H, 736; N, 9.96. α!_(D) ²⁵ =-6.40° (c=1, MeOH).

EXAMPLE 20

4bromo-3-(2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

20a. 3-pyridyl diethylcarbamate

To a refluxing solution of 3-pyridinol (9.7 g, 0.10 mol) andtriethylamine (17.0 mL, 0.12 mol) in anhydrous benzene (300 mL) wasslowly added a solution of N,N-dimethylcarbamyl chloride (14.4 mL, 0.11mol) in anhydrous benzene (50 mL). After heating at reflux for 12 hours,the resultant mixture was filtered, and the salt was washed with benzene(3×10 mL). The filtrate was concentrated and distilled under reducedpressure to provide 18.4 g (95% yield) of the title compound as a lightyellow oil (lit: bp 91-93° C./3.5 mmHg, Millner, O. E, Jr.; Stanley, J.W; Purcell, W. P. J. Med. Chem. 1974,17,13). TLC R_(f) 0.57(10:1 CHCl₃/MeOH). MS (DCI/NH₃) m/e 212 (M+NH₄)⁺, 195 (M+H)⁺. ¹ H NMR (CDCl₃, 300MHz) δ: 8.44 (d, J=0.9 Hz, 1H, ArH), 8.43 (dd, J=4.8, 1.8 Hz, 1H, ArH),7.53 (ddd, J=7.5, 1.8, 0.9 Hz, 1H, ArH), 7.30 (dd, J=7.5, 4.8 Hz, 1H,ArH), 3.43 (q, J=7.2 Hz, 2H, NCH₂), 3.40 (q, J=7.2 Hz, 2H, NCH₂), 1.27(t, J=7.2 Hz, 3H, CH₃), 1.21 (t, J =7.2 Hz, 3H, CH₃).

20b. 4bromo-3-pyridyl diethylcarbamate

To a cooled (-78° C.) solution of TMEDA (787 mg, 6.6 mmol) in anhydrousTHF (15 mL) was slowly added sec-butyl lithium (130 M, 5.08 mL, 6.6mmol), and the resultant solution was stirred at -78° C. for 10 minutes.3-Pyridyl diethylcarbamate (1.16 g, 6.0 mmol, from step 20a) in THF (3mL) was slowly added, and the mixture was stirred at -78° C. for 30minutes. 1,2-Dibromoethane (0.575 mL, 6.6 mmol) was then added, and themixture was stirred for an additional 2 hours. Brine (1 mL) was addedand the mixture was slowly warmed up to room temperature. The organiclayer was decanted, and the residue was washed with ethyl acetate (3×5mL). The combined organic layers were dried (Na₂ SO₄) and concentratedunder reduced pressure. The crude product was purified by flashchromatography on silica gel eluting with hexane/EtOAc (1:1 and 1:2) toprovide 1.25 g (76% yield) of the title compound. TLC Rf 0.48 (1:2hexane/EtOAc). MS (DCI/NH₃) m/e 290 with ⁷⁹ Br and 292 (M+NH₄)⁺ with ⁸¹Br, 273 with ⁷⁹ Br and 275 (M+H)^(+with) ⁸¹ Br. ¹ H NMR (CDCl₃, 300 MHz)δ: 8.47 (s, 1H, ArH), 8.27 (d, J=7.2 Hz, 1H, ArH), 7.16 (d, J=7.2 Hz,1H, ArH), 3.52 (q, J=7.5 Hz, 2H, NCH₂), 3.41 (q, J=7.5 Hz, 2H, NCH₂),1.33 (t, J=7.5 Hz, 3H, CH₃), 1.24 (t, J=7.5 Hz, 3H, CH₃).

20c. 4-bromo-3-pyridinol

To a solution of 4bromo-3-pyridyl diethylcarbamate (1.24 g, 4.50 mmol)in methanol (10 mL) was added sodium methoxide in methanol (2.04 g, 9.40mmol), and the resultant mixture was refluxed for 1.5 hours. Afterremoval of MeOH, EtOAc (15 mL) and water (1 mL) were added, the pH wasthen adjusted to 9 using 20% H₂ SO₄. The organic layer was decanted, andthe residue washed with EtOAc (3×5 mL). The combined organic layers weredried (Na₂ SO₄) and concentrated. The crude product was purified byflash chromatography on silica gel eluting with hexane/EtOAc (1:1 and1:2) to provide 691 mg (89% yield) of the title compound. TLC R_(f) 0.38(1:2 hexane/EtOAc). MS (DCI/NH₃) m/e 174 with ⁷⁹ Br and 176 (M+H)⁺ with⁸¹ Br. ¹ H NMR (CDCl₃, 300 MHz) δ: 8.43 (d, J =1.5 Hz, 1H, ArH), 8.02(d, J=7.2 Hz, 1H, ArH), 7.54 (dd, J=7.2, 1.5 Hz, 1H, ArH).

20d. 4bromo-3-(2-(S)pyrrolidinylmethoxy)pyridine

(S)-1-t-Butoxycarbonyl-2-pyrrolidinemethanol (792 mg, 3.94 mmol),4-bromo-3-pyridinol (685 mg, 3.94 mmol), DEAD (485 uL, 4.33 mmol) andPPh3 (1.14 g, 4.33 mmol) were allowed to react as described in Example2a The crude product was directly treated with trifluoroacetic acid (5mL) at room temperature for 3 hours. The trifluoroacetic acid wasremoved under reduced pressure, and water (8 mL) was added. The mixturewas extracted with EtOAc (2×20 mL), and the resultant aqueous layer wasbasified with excess solid sodium bicarbonate. The resultant slurry waswashed extensively with EtOAc (4×10 mL). The combined organic layerswere dried (Na₂ SO₄) and evaporated. The crude product was purified byflash chromatography on silica gel eluting with CHCl₃ /MeOH/NH₄ OH(10:1.5:0.02 and 10:1.5:0.1) to provide 371 mg (37% yield from4bromo-3-pyridinol) of the title compound. TLC R_(f) 0.16 (10:1:0.02CHCl₃ /MeOH/NH₄ OH). MS (DCI/NH₃) m/e 257 with ⁷⁹ Br and 259(M+H)^(+with) ⁸¹ Br. ¹ H NMR (CDCl₃, 300 MHz) 8: 8.25 (s, 1H, ArH), 8.08(d, J=6.6 Hz, 1H, ArH), 7.48 (d, J=6.6 Hz, 1H, ArH), 4.28 (dd, J =4.8,10.2 Hz, 1H, OCHH), 4.17 (dd, J=6.3, 10.2 Hz, 1H, OCHH), 3.90-3.80 (m,1H, NCH), 3.30-3.14 (m, 2H, NCR₂), 2.18-1.80 (m, 4H, 2CH₂).

20e. 4-bromo-3-(2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

The compound of step 20d (140 mg) was treated with HCl and isolated asdescribed in Example 1b to afford 120 mg (67% yield) of the titlecompound as a light yellow powder. mp 191-193° C. MS (DCI/NH₃) m/e 257with ⁷⁹ Br and 259 (M+H)^(+with) ⁸¹ Br. ¹ H NMR (D₂ O,300 MHz) δ: 8.28(s, 1H, ArH), 8.09 (d,J=5.2 Hz, 1H, ArH), 7.77 (d, J=5.2 Hz, 1H, ArH),4.61 (dd, J =3.3, 10.7 Hz, 1H, OCHH), 4.36 (dd, J=7.4, 10.7 Hz, 1H,OCHH), 4.24-4.16 (m, 1H, NCH), 3.52-3.37 (m, 2H, NCH₂), 2.38-1.98 (m,4H, 2CH₂). Anal. Calc. for C₁₀ H₁₅ N₂ OCl₂ Br: C, 36.39; H, 4.58; N,8.49. Found: C, 36.00; H, 4.24; N, 8.38.

EXAMPLE 21

4bromo-3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine dihydrochloride

21a. 4bromo-3-((1-methyl-2-(S)-pyrrolidinyl)methoxypyridine (74)

The compound of Example 20d above (225 mg) was treated with formic acidand formaldehyde and isolated as described in Example 16a to afford 40mg (18% yield) of the title compound. TLC R_(f) 0.37 (10:1CHCl₃ /MeOH).MS (DCI/NH₃) m/e 271 with ⁷⁹ Br and 273 (M+H)^(+with) ⁸¹ Br. ¹ H NMR(CDCl₃, 300 MHz) δ: 8.24 (s, 1H, ArH), 8.07 (d, J=6.3 Hz, 1H, ArH), 7.48(d, J=6.3 Hz, 1H, ArH), 4.34-4.03 (m, 3H), 3.35-2.80 (m, 2H), 2.14 (s,3H, CH₃), 2.35-1.70 (m, 4H, 2CH₂).

21b. 4bromo-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridinedihydrochloride

The compound of step 21a (35 mg) was treated with HCl and isolated asdescribed in Example 1b to afford 43 mg (96% yield) of the titlecompound as a light yellow powder. mp 191-193° C. MS (DCI/NH₃) m/e 271with ⁷⁹ Br and 273 (M+H)⁺ with ⁸¹ Br. ¹ H NMR (D30,300 MHz) δ: 8.32 (s,1H, ArH), 8.14 (d, J=5.3 Hz, 1H, ArH), 7.87 (d, J=5.3 Hz, 1H, ArH), 4.69(dd, J=3.3, 11.4 Hz, 1H, OCHH), 4.42 (dd, J=7.0, 11.4 Hz, 1H, OCHH),4.08-3.98 (m, 1H, NCH), 3.83-3.76 (m, 1H, NCH), 332-3.22 (m, 1H, NCH),3.14 (s, 3H, NCH3), 2.44-2.02 (m, 4H, 2CH₂). Anal. Calc. for C₁₁ H₁₇ N₂OCl₂ BrΩ0.10 Et₂ O: C, 38.96; H, 5.16; N, 7.93. Found: C, 39.22; H,4.94; N, 8.28.

EXAMPLE 22

3-((cis-1,5-dimethyl-2-(S)-pyrrolidinyl)methoxy)pyridinedihydrochloride

22a. 3-((5-oxo-2-(S)-pyrrolidinyl)methoxy)pyridine

To a solution of triphenylphosphine (52.46 g, 0.20 mol) in 400 mL ofanhydrous THF at 0° C. was added diethyl azodicarboxylate (31.49 mL,0.20 mol) dropwise. The mixture was stirred at 0° C. for 30 minutes,then brought to room temperature. (S)-5(Hydroxymethyl)-2-pyrrolidinone(Aldrich Chemical Co., 15.19 g, 0.13 mol) and 3-hydroxypyridine (19.02g, 0.20 mol) were added to the reaction vessel, and stirred for 16hours. Solvent was removed in vacuo. The residue was diluted with CH₂Cl₂ and washed with 1N NaOH. After a brine wash (2×), the organic layerwas dried over MgSO₄. The residue was purified by silica gel flashchromatography using a gradient from 100% CHCl₃ to 10% MeOH/CHCl₃(purification system was run twice), then recrystallized with ethylacetate to give 4.0 g (16%) of the title compound as a white powder,mp.=121-122° C. TLC R_(f) =0.31 (10%MeOH/CHCl₃). MS (DCI/NH₃) m/e: 193(M+H)⁺ and 210 (M+NH₄)₊. ¹ H NMR (CDCl₃, 300 MHz) δ: 8.32-8.30 (m, 111),8.27 (dd, J=4.40, 1.50 Hz, 1H), 7.25-7.16 (m, 2H), 6.17 (br s, 1H),4.14-4.08 (m, 1H), 4.05 (dd, J=8.80, 3.70 Hz, 1H), 3.89 (dd, J=8.80,7.70 Hz, 1H1), 2.49-2.23 (m, 3H), 1.99-1.87 (m, 1H). Anal. Calc. for C₁₀H₁₂ N₂ O₂ : C, 62.49; H, 6.29; N, 14.57; Found C, 62.53; H, 6.25; N,14.71.

22b. 3-((1-methyl-5-oxo-2-(S)-pyrrolidinyl)methoxy)pyridine

To a solution of the compound from step 22a above (0.100 g, 0.52 mmol)in anhydrous THF at 0° C. was added NaH (80% dispersion, 0.02 g, 0.83mmol) was added, and the reaction mixture was stirred for 20 minutes atthis temperature. The reaction was then warmed to room temperature, andiodomethane (0.06 mL, 0.89 mmol) was added via syringe. After startingmaterial was consumed, NaHCO₃ was added to the reaction followed by CH₂CI₂. The desired compound was extracted from the aqueous phase, and theorganic layer was subjected to a brine wash (2×). The organic layer wasdried over MgSO₄. The residue was purified by silica gel flashchromatography (5% MeOHI/CHCl₃) to give 0.107 g (100%) of the titlecompound as a white powder. mp.=73-74° C. MS (DCI/NH₃) m/e: 207 (M+H)⁺and 224 (M+NH₄)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ: 8.33-8.28 (m, 2H),7.24-7.18 (m, 2H), 4.14 (dd, J=9.50, 4 Hz, 1H), 4.04 (dd, J=9.50, 4.40Hz, 1H), 3.95-3.89 (m, 1H), 2.92 (s, 3H), 2.55-2.50 (m, 1H), 2.45-2.21(m, 2H), 2.02-1.94 (m, 1H). Anal. Calc. for C₁₁ H₁₄ N₂ O₂ : C, 64.06; H,8.84; N, 13.58; Found C, 64.07; H, 6.67; N, 13.67. α!_(D) ²⁵ =+37.30°(c=1.03, MeOH).

22c. 3-((cis-1 5-dimethyl-2-(S)-pyrrolidinyl)methoxy)pyridine

To a solution of the compound of step 22b above (0.400 g, 1.94 mmol) inanhydrous THF at 0° C. was added Methyl/MgCl (Aldrich Chemical Co., 3Msolution in THF, 1.94 mL, 5.80 mmol). An immediate precipitate formed inthe reaction, but the reaction was stirred at this temperature for 2hours. The reaction was then brought to room temperature and sonicatedfor 30 minutes followed by stirring for an hour. After the startingmaterial was consumed the reaction was quenched with MeOH. Bromocresolgreen indicator was added followed by enough 2N HCl/MeOH to turn thecolor of the reaction mixture yellow (acidic pH). Sodiumcyanoborohydride (0.182 g, 2.92 mmol) was added to the reaction and themixture was stirred for an additional 3 hours (adding 2N HCl/MeOH tomaintain the pH). Saturated K₂ CO₃ was added to the reaction mixtureslowly. After the aqueous phase tested basic, CH₂ Cl₂ was added toextract the desired material. The organic layer was then washed with abrine solution (2×) and dried over MgSO₄, The resulting material waspurified by silica gel flash chromatography (10%MeOH/CHCl₃) to give0.170 g (42.5%) of the cis-5'-methyl compound and 0.057 g (14%) of thetrans -5'-compound (the data for the cis compound given). MS (DCI/NH₃)m/e: 207 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ: 8.32 (m, 1H), 8.20 (t, J=3Hz, 1H), 7.20-7.18 (m, 2H), 4.05 (dd, J=9.20, 5.50 Hz, 1H), 3.89 (dd,J=9.20, 6.25 Hz, 1H), 2.80-2.75 (m, 1H), 2.41 (s, 3H), 2.40-2.37 (m,1H), 2.01-1.87 (m, 2H), 1.65-1.61 (m, 1H), 1.47-1.44 (m, 1H), 1.13 (d,J=6.25 Hz, 3H).

22d. 3-((cis-1 dimethyl-2-(S)-pyrrolidinyl)methoxy)pyridinedihydrochloride

The free base from step 22c above was dissolved in diethyl ether andbrought to 0 ° C. with stirring. The solution was treated with diethylether saturated with hydrogen chloride gas. The solvent was removed invacuo. The resulting salt was triturated with diethyl ether (2×) anddried under vacuum to give a white powder. MS (DCI/NH₃) m/e: 207 (M+H)⁺.¹ H NMR (D₂ O,300 MHz) δ: 8.41 (br s, 1H), 8.31 (d, J=4.40 Hz, 1H),7.81-7.77 (m, 11), 7.66 (dd, J=8.80, 5.10 Hz, 1H), 4.57 (dd, J=11.40, 3Hz, 1H), 4.44 (dd, J=8.80, 5.90 Hz, 1H), 4.03-3.96 (m, 1H-1), 3.61-3.53(m, 1H), 3.03 (s, 3H), 2.43-2.30 (m, 2H), 2.14-2.03 (m, 1H), 1.92-1.81(m, 1H), 1.47 (d, J=6.6 Hz, 3H). Anal. Calc. for C₁₂ H₁₈ N₂ _(O)Ω 2.20HCl: C, 50.31; H, 7.11; N, 9.78; Found C, 50.07; H, 7.10; N, 9.77.α!_(D) ²⁵ =+8.60° (c=1, MeOH).

EXAMPLE 23

3-((trans-1-methyl-4hydroxy-2(S)-pyrrolidinyl)methoxypyridinedihydrochloride

23a.3-((trans-1-methyl-4-hydroxy-oxo-2(S)-pyrrolidinyl)methoxy)pyridine

A sample of the compound (1.0 g, 5.6 mmol) from Example 22b wasdissolved in 25 mL of THF and cooled to -78° C. Lithium diisopropylamide (LDA) solution (1.5 M in hexane, 7.5 mL, 11.2 mmol) was added, andthe solution was stirred at -78° C. for 30 min. Next a solution of 1.17g (5.12 mmol) of (+)-(camphorsulfonyl)oxaziridine in 24 mL of THF wasadded. After stirring at -78° C. for 1 h, the reaction mixture wasgradually warmed to room temperature and stirred for an additional 2hours. The reaction was then quenched by addition of methanol. Theresultant mixture was stirred for 15 min, and the solvent was removed.The residue was subjected to flash chromatography on silica gel usingchloroform:methanol (10:1) as eluant. The title compound was isolated asan oil (0.76 g, 69% yield). MS m/e: 223 (M+H)⁺, 240 (M+NH₄)⁺, ¹ H NMR(CDCl₃, 300 MHz) δ: 8.37-8.26 (m, 2H), 7.31-7.16 (m, 2H), 4.59 (t, J=7.5Hz, 1H,), 4.18 (dd, J=4.5, 9 Hz, 1H), 4.04 (dd, J=4.5, 9 Hz, 1i),3.96-3.88 (m, 1H), 2.96 (s, 3H), 2.52-2.42 (m, 1H), 2.21-1.98 (m, 1H).

23b.3-((trans-1-methyl-4-hydroxy-2(S)-pyrrolidinyl)methoxy)pyridine

To the compound of step 23a (275 mg, 1.24 mmol) in 5 mL of THF wasadded, under nitrogen and dropwise over a period of 5 minutes, 2.5 mL(2.48 mmol) of a 1 M solution of borane in THF. After stirring underreflux for 3 hours, methanol was added dropwise, and the reaction wasstirred for an additional 15 minutes. The solvent was then removed invacuo, affording a white solid borane complex. This solid was dissolvedin anhydrous ethanol. Cesium fluoride (0.286 g, 2.48 mmol) was added,and the resultant solution was stirred under reflux for 16 hr.Evaporation of the solvent provided a white solid which was purified ona silica gel column, eluting with chloroform:methanol (10:1) to give 220mg of the desired alcohol as an oil in 85% yield. TLC R_(f) =0.38 (10:1CHCl₃ : MeOH). MS m/e: 209 (M+n)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ:8.35-8.33 (m, 1H), 8.25-8.21 (m, 1H), 7.24-7.20 (m, 2H), 4.54-4.44 (m,1H), 4.08-3.97 (m, 2H), 3.52-3.44 (m, 1H), 3.08-2.99 (m, 1H), 2.51 (s,3H), 2.43-2.33 (m, 1H), 2.14-1.97 (m, 2H).

23c.3-((trans-1-methyl-hydroxy-2(S)-pyrrolidinyl)methoxy)pyridinedihydrochloride

A solution of HCl in ether was added dropwise to a stirred solution ofcompound 23b (220 mg, 1.05 mmol) in diethyl ether at room temperature.The resultant white precipitate was then collected by centrifugation andtriturated with three portions of diethyl ether. The hygroscopic solidwas obtained in 59% yield (174 mg). mp 145-147° C. MS m/e (DCI/NH₃): 209(M+H)⁺, 226 (M+NH₄)⁺. ¹ H NMR (D₂ O,300 MHz) 5: 8.42 (d, J=2.6 Hz, 1H),8.32 (d, J=4.4 Hz, 1H), 7.77-7.85(m, 1H), 7.66 (dd, J=5.1, 8.4 Hz, 1H),4.64 (dd, J=4.6, 11.0 Hz, 1H), 4.44 (dd, J=5.9, 11.4 Hz, 1H), 4.34-4.21(m, 1H), 4.04-3.89 (m, 1H), 3.20-3.11 (m, 1H), 3.34-3.03 (m, 1H), 3:15(s, 3H), 2.38-2.34 (m, 2H). Anal. Calc.. for C₁₁ H₁₆ N₂ O₂Ω 1.9HCl-0.1H₂ O: C, 47.30; H, 6.53; N, 10.01. Found: C, 47.63; H, 6.42; N,9.68. α!_(D) =+2.2° (c 0.41, MeOH).

EXAMPLE 24

3-((trans-1,4dimethyl-2(S)-pyrrolidinone)methoxy)pyridinedihydrochloride

24a. 3-((trans-1.4dimethyl-5-oxo-2(S)-pyrrolidinyl)methoxy) pyridine

A sample of lactam (0.17 g, 0.83 mmol) from Example 22b was dissolved in5 mL of THF and cooled to -78° C. Lithium diisopropyl amide (LDA)solution (1.5 M in hexane, 1.11 mL, 1.66 mmol) was added, and thesolution was stirred at 0° C. for 30 min. After cooling to -78° C., Me(0.1 mL, 1.66 mmol) was added, and the resultant solution was stirred at-78° C. for 3 hours. The reaction was then quenched by addition ofsaturated ammonium chloride aqueous solution. The resultant mixture wasstirred for 15 min, and the aqueous layer was extracted with ethylacetate. The combined organic layers were then dried over anhydrousmagnesium sulfate. Filtration and concentration under vacuum provided ayellow oil, which was subjected to flash chromatography on silica gelusing chloroform:methanol (10:1) as eluant. The title compound wasisolated as an oil (0.13 g, 75% yield). TLC R_(f) =0.10 (100:1 CHCl₃ :MeOH). MS m/e: 221 (M+H)⁺, 238 (M+NH₄)⁺. ¹ H NMR (CDCl₃,300 MHz) δ:8.37-8.22 (m, 2H), 7.35-7.23(m, 2H), 4.09 (ddd, J=4.5, 9.0, 15 Hz, 2H,),3.89-3.81(m, 1H), 2.93 (s, 3H), 2.73-2.60 (m, 1H), 2.29-2.20 (m,1H),1.23 (d, J=8 Hz, 3H).

24b.3-((trans-1.4dimethyl-2(S)-pyrrolidinyl)methoxy)pyridine

To the compound of step 24a (130 mg, 0.63 mmol) in 4 mL of THF wasadded, under nitrogen and dropwise over a period of 5 minutes, 1.25 mL(1.25 mmol) of a 1 M solution of borane in THF. After stirring underreflux for 2 hours, methanol was added dropwise and the reaction wasstirred for an additional 15 minutes. The solvent was then removed invacuo, affording a white solid borane complex. This solid was dissolvedin anhydrous ethanol. Cesium fluoride (0.218 g, 1.89 mmol) was added,and the resultant solution was stirred under reflux for 16 hr.Evaporation of the solvent provided a white solid which was purified ona silica gel column, eluting with chloroform:methanol (10:1) to give 59mg of the desired methyl compound as an oil in 46% yield. TLC R_(f)=0.16 (10:1CHCl₃ : MeOH). MS m/e: 207 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz)8: 8.34 (brs, 1H), 8.26-8.18 (m, 1H), 7.25-7.18 (m, 2H), 4.20-4.02 (m,1H), 4.02-3.90 (m, 1H), 3.33-3.21 (m, 1H), 3.00-2.80 (m, 1H), 2.54 (s,3H), 2.45-2.30 (m, 1H), 2.12-1.91 (m, 2H), 1.74-1.54 (m, 1H), 1.06 (d,J=8.0 Hz).

24c. 3-((trans-11.4dimethyl-2(S)-pyrrolidinyl)methoxy)pyridinedihydrochloride

A solution of HCl in ether was added dropwise to a stirred solution ofcompound 24b (55 mg, 0.27 mmol) in diethyl ether at room temperature.The resultant white precipitate was then collected by centrifugation andtriturated with three portions of diethyl ether. The hygroscopic solidwas obtained in 56% yield (42 mg). mp 223-225° C. MS m/e (DCI/NH₃): 207(M+H⁺). ¹ H NMR (DMSO-d₆,300 MHz) δ: 8.65 (d, J=2.9 Hz, 1H), 8.46 (d,J=5.9 Hz, 1H), 8.00 (dd, J=2.3, 8.7 Hz, 1H), 7.81 (dd, J=5.2, 8.7 Hz,1H), 4.60 (dd, J=8.1, 11.0 Hz, 1H), 4.49 (dd, J=3.5, 10.4 Hz, 1H),4.04-3.95 (m, 1H), 3.64-3.58 (m, 1H), 2.92 (s, 3H), 2.80-2.74 (m, 1H),2.45-2.40 (m, 1H), 2.04-1.98 (m, 11i), 1.95-1.89 (m, 1H), 1.07 (d, J=6.9Hz, 3H). Anal. Calc. for C₁₂ H₁₈ N₂ OΩ2.0 HCl: C, 51.62; H, 7.22; N,10.03. Found: C, 51.84; H, 7.36; N, 9.90. α!_(D) =-2.3° (c=0.32, MeOH).

EXAMPLE 25

3-((trans-1-methylethyl-2-(S)-pyrrolidinyl)methoxy pyridinedihydrochloride

25a.3-((trans-1-methyl-4ethyl-5-oxo-2(S)-pyrrolidinyl)methoxy)pyridine

A sample of lactam (0.195 g, 0.94 mmol) from Example 22b was dissolvedin 3 mL of THF and cooled to -78° C. Lithium diisopropyl amide (LDA)solution (1.5 M in hexane, 0.94 mL, 1.42 mmol) was added and thesolution was stirred at -78° C. for 30 min. EtI (0.113 mL, 1.42 mmol)was then added and the resultant solution was stirred at -78 ° C. for 3hours and gradually warmed to room temperature. The reaction wasquenched by addition of saturated ammonium chloride aqueous solution.The resultant mixture was stirred for 15 min and the aqueous layer wasextracted with ethyl acetate. The combined organic layers were thendried over anhydrous magnesium sulfate. Filtration and concentrationunder reduced pressure provided a yellow oil which was subjected toflash chromatography on silica gel using chloroform:methanol (10:1) aseluant. The title compound was isolated as an oil (0.216 g, 98% yield).TLC R_(f) =0.42 (10:1 CHCl₃ :MeOH). MS m/e: 235 (M+H)⁺. ¹ H NMR (CDCl₃,300 MHz) δ: 8.35-8.29 (m, 1H), 8.30-8.25 (m, 1H), 7.25-7.16 (m, 2H),4.18-4.00 (m 2H), 3.89-3.75 (m, 1H1), 2.94 (s, 3H), 2.62-2.48 (m, 1H),2.23-2.12 (m, 1H),.2.00-1.80 (m, 21H), 1.70-1.30 (m, 2H1), 0.98 (t,J=7.5 Hz, 3H).

25b.3-((trans-1-methylethlyl-2(S)-pyrrolidinyl)methoxy)pyridine

To the compound of step 25a (230 mg, 0.63 mmol) in 2 mL- of THF wasadded under nitrogen and dropwise over a period of 5 minutes 2.95 mL(2.95 mmol) of a 1 M solution of borane in THF. After stirring underreflux for 3 hours, methanol was added dropwise and the reaction stirredfor an additional 15 minutes. The solvent was then removed in vacuo,affording a white solid borane complex. This solid was dissolved inanhydrous ethanol. Cesium fluoride (0.335 g, 2.95 mmol) was added, andthe resultant solution was stirred under reflux overnight. Evaporationof the solvent provided a white solid which was purified on a silica gelcolumn, eluting with chloroform:methanol (10:1) to give 104 mg of thedesired methyl compound as an oil in 48% yield. TLC R_(f) =0.14 (10:1CHCl₃ : MeOH). MS m/e: 221 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ:8.35-8.31 (m, 1H), 8.24-8.19 (m, 1H), 7.24-7.18 (m, 2H), 4.08-3.86 (m,2H), 3.25-3.15(m, 1H), 2.80-2.66 (m, 1H), 2.47 (s, 3H), 2.20-2.04 (m,1H), 1.99 (dd, J=9.0, 9.6 Hz, 1H), 1.95-1.85 (m, 1H), 1.72-1.57 (m, 2H),1.48-1.31 (m, 2H), 0.92 (t, J=8.0 Hz

25c. 3-((trans-1-methylethyl-2(S) -pyrrolidinyl)methoxy)pyridinedihydrochloride

A solution of hydrochloride in ether was added dropwise to a stirredsolution of compound 25b (55 mg, 0.27 mmol) in diethyl ether at roomtemperature. The resultant white precipitate was then collected bycentrifugation and triturated with three portions of diethyl ether. Thehygroscopic solid was obtained in 56% yield (42 mg). mp 219-220° C. MSm/e (DCI/NH₃): 221 (M+H⁺). ¹ H NMR (D₂ O, 300 MHz) 8: 8.45 (d, J=2.6 Hz,1H), 8.36 (d, J=5.1 Hz, 1H), 7.91 (m, 1H), 7.76 (dd, J=5.2, 8.8 Hz, 111,4.59 (dd, J=2.9, 11.0 Hz, 11H), 4.43 (dd, J=5.9, 11.0 Hz, 1H), 4.04-3.95(m, 1H), 4.08-4.00 (m, 1H), 3.83 (dd, J=6.6, 11.0 Hz), 3.05 (s, 3H),2.95 (t, J=11.0 Hz, 1H), 2.45-2.00 (m, 2H), 2.14-2.03 (m, 1H), 1.60-1.45(m, 211), 0.94 (t, J=7.4 Hz, 3H). Anal, Calcd. for C₁₃ H₂ ON₂ OΩ1.9 HCl:C, 53.92; H, 7.62; N, 9.67. Found: C, 54.00; H, 7.59; N, 9.35. α!_(D)=-1.9 (c 0.37, MeOH).

EXAMPLE 26

3-((1-methyl-2-piperidinyl)methoxy)pyridine oxalate salt

1-Methyl-2-piperidinemethanol (0.857 g, 6.65 mmol) was allowed to reactwith 3-bromopyridine (0.67 mL, 6.98), cuprous bromide (0.257 g, 1.33mmol), triphenylphosphine (0.698 g, 2.66 mmol) and potassium carbonate(0.919 g, 6.65 mmol). The reaction mixture was heated to 90° C. andstirred for 120 hr, then cooled to 25° C., acidified with HCl (1.5 M; 35mL) and washed with ethyl acetate (4×50 mL). The aqueous layer wasbasified with saturated aqueous potassium carbonate, and the product wasextracted with chloroform (6×100 mL), dried (MgSO₄) and concentrated invacuo to an oil. The crude product was purified to yield the free baseof the title compound after chromatography on silica gel (CHCl₃/MeOH/NH₄ OH 1500:30:3). The amine was dissolved in EtOH (1 mL) andtreated with oxalic acid (ca. 65 mg) to yield after recrystallization(EtOH/Et₂ O) the title compound (0.088 g, 4%) as a hygroscopic whitesolid. MS (DCI/NH₃) m/e: 207 (M+H)⁺. ¹ H NMR (D₂ O,300 MHz) 5: 8.46 (d,J=2.9 Hz, 1H), 8.37 (dd, J=5.2, 1.1 Hz, 1H), 7.94 (ddd, J=8.8, 2.9, 1.1Hz, 1H), 7.80 (dd, J=8.8, 5.9 Hz, 1H), 4.69 (dd, J=11.2, 3.1 Hz, 1H),4.35 (dd, J=11.2, 2.0 Hz, 1H), 3.56 (m, 2H), 3.18 (dt, J=12.7, 3.0 Hz,1H), 2.93 (s, 3H), 2.05-1.65 (m, 6H). Anal. calcd for C₁₄ H₂₀ N₂ O₅ Ω0.4C₂ H₂ O₄ : C, 53.49; H, 6.31; N, 8.43. Found: C, 53.39; H, 6.09; N,8.19.

EXAMPLE 27

4-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

27a. 4-methyl-3-pyridyl diethylcarbamate

To the cooled (-78° C.) solution of TMEDA (516.5 mg, 4.40 mmol) inanhydrous THF (10 mL) was slowly added sec-butyl lithium (1.3 M, 3.38mL, 4.40 mmol), and the resultant solution was stirred at -78° C. for 10minutes. 3-Pyridyl diethylcarbamate (776 mg, 4.0 mmol) in THF (3 mL) wasslowly added, and the mixture was stirred at -78° C. for 30 minutes.Iodomethane (275.4 μL, 4.40 mmol) was then added, and the mixture wasstirred for two hours. Brine (1 mL) was added, and the mixture wasslowly warmed up to room temperature. The organic layer was decanted,and the residue washed with ethyl acetate (3×5 mL). The combined organiclayers were dried (Na₂ SO₄) and concentrated. The crude product waspurified by chromatography on silica gel eluting with hexane/EtOAc (1:2and 0:1) to provide 765 mg (92% yield) of the title compound. TLC R_(f)0.28 (1:2 hexane/EtOAc). MS (DCI/NH₃) m/e 209 (M+H)⁺. ¹ H NMR (CDCl₃,300 MHz) δ: 8.34 (s, 1H, ArH), 8.32 (d, J=6.9 Hz, 1H, ArH), 7.16 (d,J=69 Hz, 1H, ArH), 3.48 (q, J=7.5 Hz, 2H, NCH₂), 3.41 (q, J=7.5 Hz, 2H,NCH₂), 1.28 (t, J=7.5 Hz, 3H, CH3), 1.22 (t, J=7.5 Hz, 3H, CH₃).

27b. 4methyl-3-pyridinol

To the solution of 4-methyl-3-pyridyl diethylcarbamate (760 mg, 3.65mmol) in methanol (10 mL) was added sodium methoxide (623 mg, 11.0mmol), and the resultant mixture was refluxed for 20 hours. Methanol wasevaporated, EtOAc (15 mL) and water (1 mL) were added, pH was adjustedto 9 using 20% yield H2SO₄. Organic layer was decanted and the residuewashed with EtOAc (3×5 mL). The combined organic layers were dried (Na₂SO₄) and concentrated. The crude product was purified by flashchromatography on silica gel eluting with CHCl₃ /MeOH (20:1 and 10:1) toprovide 325 mg (82% yield) of the title compound. TLC R_(f) 030 (10:1CHCl₃ /MeOH). MS (DCI/NH₃) m/e 110 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ:8.24 (s, 1H, ArH), 7.98 (d, J=7.2 Hz, 1H, ArH), 7.16 (d, J=7.2 Hz, 1H,ArH).

27c. 4methyl-3-(2-(S)-pyrrolidinylmethoxypyridine

(S)-1-t-Butoxycarbonyl-2-pyrrolidinemethanol (590 mg, 2.94 mmol),4-methyl-3-pyridinol (320 mg, 2.94 mmol), DEAD (509 uL, 3.23 mmol) andPPh3 (848 mg, 3.23 mmol) in THF (100 mL) were allowed to react asdescribed in Example 2a Solvent was removed, and the residue waschromatographed with CHCl_(3/) MeOH (10:1) to provide 1.8 g of the crudemixture. This material was immediately treated with trifluoroacetic acid(2.0 mL) at room temperature for 3 hours, and excess trifluoroaceticacid was removed under reduced pressure. Water (3 mL) and EtOAc (20 mL)were added, and the mixture was stirred for 5 minutes. The organic layerwas decanted, and the residue washed with EtOAc (3×10 mL). The combinedorganic layers were dried (Na₂ SO₄) and evaporated. The crude productwas purified by flash chromatography on silica gel eluting with CHCl₃/MeOH/NH₄₀ H (10:1:0.02 and 10:1.5:0.1) to provide 52 mg (14% yield from4methyl-3-pyridinol) of the title compound TLC R_(f) 0.18 (10:1:0.02CHCl₃ /MeOH/NH₄ OH). MS (DCI/NH₃) m/e 193 (M+H)⁺. ¹ H NMR (CDCl₃,300MHz) δ: 8.16 (s, 1H, ArH), 8.12 (d, J=6.9 Hz, 1H, ArH), 7.07 (d,J=6.9 Hz, 1H, ArH), 4.12-4.00 (m, 2H, OCH₂), 3.75-3.63 (m, 1H, NCH),3.18-3.02 (m, 2H, NCH₂), 2.24 (s, 3H, NCH3), 2.08-1.64 (m, 4H, 2CH₂).

27d. 4Methyl -3-(2-(S)-pyrrolidinylmethoxypyridine dihydrochloride

The compound of step 27c was treated with HCl and isolated as describedin Example 1b to afford a cream colored powder. MS (DCI/NH₃) m/e 193(M+H)⁺. ¹ H NMR (D₂ O,300 MHz) δ: 8.34 (s, 1H, ArH), 8.33 (d, J=5.5 Hz,1H,ArH), 7.82 (d, J=5.5 Hz, 1H, ArH), 4.60 (dd, J=3.3, 10.3 Hz, 1H,OCHH), 4.37 (dd, J=7.4, 10.3 Hz, 1H, OCHH), 4.25-4.17 (m, 1H, NCH), 3.44(t, J =7.4 Hz, 2H, NCH₃), 2.50 (s, 3H, NCH₃), 2.40-1.98 (m, 4H, 2CH₂).Anal. Calc. for C₁₁ H₁₈ N₂ OCl₂ Ω0.30 HCl: C, 47.85; H, 6.76; N, 10.21.Found: C, 48.01; H, 6.44; N, 10.19.

EXAMPLE 28

5-bromo-3-((1-methyl-2-(S) pyrrolidinyl)methoxy)pyridine dihydrochloride

28a. 5-bromo-3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)pyradine

(S)-1-Methyl-2-pyrrolidinemethanol (4.96 g, 40.0 mmol) was carefullyadded to the suspension of sodium hydride (1.32 g, 80% yield, 44.0 mmol)in anhydrous DMF (100 mL). After stirring at room temperature for 0.5hour, 3,5-dibromopyridine (4.83 g, 20.0 mmol) was added, and thereacting mixture was stirred at 50° C. for 4 hours. Another 5.0 mL ofwater was added, and the solvents were removed under reduced pressure.Again, water (5.0 mL) was added, and the slurry was washed extensivelywith EtOAc (4×40 mL). The combined organic layers were dried (Na₂ SO₄)and concentrated. The crude product was purified by flash chromatographyon silica gel eluting with CHCl₃ /MeOH (10.1) to provide 4.50 g (83%yield) of the title compound. TLC R_(f) 0.33 (10:1 CHCl_(3/) MeOH). MS(DCI/NH₃) m/e 271 with ⁷⁹ Br and 273 (M+H)⁺ with ⁸¹ Br. ¹ H NMR (CDCl₃,300 MHz) δ: 8.37 (d, J=1.8 Hz, 1H, ArH), 8.26 (d, J=2.7 Hz, 1H, ArH),7.39 (dd, J=1.8, 2.7 Hz, 1H, ArH), 4.01 (dd, J=3.3,11.1 Hz, 1H, OCHH),3.93 (dd, J=6.9, 11.1 Hz, 1H, OCHH), 3.20-3.10 (m, 1H, NCH), 2.76-2.64(m, 1H, NCH), 2.49 (s, 3H, NCH₃), 2.40-2.28 (m, 1H, NH), 2.44-2.00 (m,4H, 2CH₂).

28b. 5-bromo-3-((1-methyl-2-(S)-pyrrolidinyl)methoxypyridinedihydrochloride

The compound of step 28a (190 mg) was treated with HCl and isolated asdescribed in Example 1b to afford 170 mg (71% yield) of the titlecompound as a light yellow powder. mp 223-225° C. MS (DCI/NH₃) m/e 271with ⁷⁹ Br and 273 (M+H)⁺ with ⁸¹ Br. ¹ H NMR (CDCl₃, 300 MHz) 5: 8.42(d, J=1.5 Hz, 1H, ArH), 8.35 (d, J =2.7 Hz, 1H, ArH), 7.93 (dd,J=1.5,2.7 Hz, 1H, ArH), 4.55 (dd, J=3.0, 11.4 Hz, 1H, OCHH), 4.38 (dd,J=6.3, 11.4 Hz, 1H, OCHH, 3.98-3.86 (m, 1H, NCH), 3.80-3.72 (m, 1H,NCH), 3.30-3.20 (m, 1H, NCH), 3.03 (s, 3H, NCH₃), 2.44-2.00 (m, 4H,2CH₂). Anal. Calc. for C₁₂ H₁₆ N₂ OClF₃ Ω0.10 Et₂ O: C, 38.96; H, 5.16;N, 7.93. Found: C, 39.05; H, 4.80; N, 8.27.

EXAMPLE 29

2-methyl-3-(2-(S)-azetidinylmethoxypyridine dihydrochloride

29a. 2-methyl-3-((1-t-Butoxycarbonyl-2-(S)-azetidinyl)methoxy)pyridine

An ice-cooled solution of 1-t-butoxycarbonyl-2-(S)-azetidinemethanol(from Example 7b, 0.623 g, 3.33 mmol) was allowed to react with2-methyl-3-hydroxypyridine (0.399 g, 3.66 mmol) under the conditions ofExample 2a to yield the title compound (0.511 g, 55%). MS (DCI/NH₃) m/e:279 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ: 8.10 (dd, J=4.4, 1.5 Hz, 1H),7.15-7.06 (m, 2H), 4.54-4.53 (m, 1H), 4.35-4.34 (m, 1M), 4.07 (dd,J=10.3, 2.6 Hz, 1H), 3.96-3.88 (m, 2H), 2.51 (s, 3H), 2.42-2.31 (m, 2H),1.40 (s, 9H).

29b. 2-methyl-3-(2-(S)-azetidinylmethoxy)pyridine dihydrochloride

The compound from step 29a (0.181 g, 0.65 mmol) was treated withsaturated ethanolic HCl (5 mL). After 4 hr, the volatiles were removedin vacuo, and the dihydrochloride was recrystallized (EtOH/Et₂ O) toyield the title compound (0.157 g, 96% yield) as a white solid. mp153-154° C. MS (DCI/NH₃) m/e: 179 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ:8.21-8.19 (d, J=5.5 Hz, 1H), 7.94 (d, J=8.4 Hz, 1H), 7.74 (dd, J=5.5,3.1 Hz, 1H), 5.04-4.93 (m, 1H), 4.61-4.50 (m, 2H), 4.21-4.08 (m, 2H),2.78-2.65 (m, 2H), 2.69 (s, 3H). Anal. calc. for C₁₀ H₁₆ Cl₂ N₂ OΩ0.8H₂O: C, 45.23; H, 6.68; N, 10.55. Found: C, 45.15; H, 6.85; N, 10.51.α!_(D) ²³ =+7.27 ° (c =0.11 in MeOH).

EXAMPLE 30

2-Methyl-3-((1-methyl-2-(S)-azetidinyl)methoxy)pyridine dihydrochloride

A 252.1 mg sample of2-methyl-3-((1-t-Butoxycarbonyl-2-(S)-azetidinyl)methoxy)pyridine, fromExample 29a above, was stirred with 2 mL of formic acid and 4 mL offormaldehyde at 90° C. for 26 hours. The solvent was removed undervacuum, and the residue was dissolved in 10% KHSO₄. This solution waswashed with ethyl acetate, made basic with aqueous K₂ CO₃ solution, thenextracted with chloroform. The extract was dried over MgSO₄ andfiltered, then the solvent was removed. The residue was chromatographedon silica gel, and the product was converted to the salt by treatmentwith ethanolic HCl. MS (DCI/NH₃) m/e: 193 (M+H)⁺. ¹ H NMR (D₂ O,300 MHz)δ: 2.62-2.74 (m, 2H), 2.66 (s, 3H), 3.03 (s, 3H), 4.03 (q, 1H), 4.34 (q,1H), 4.58-4.65 (m, 2H), 4.87-4.90 (m, 1H), 7.68 (m, 1H), 7.85 (d, 1H),8.18 (dt, 1H). Anal. calc. for C₁₁ H₁₈ Cl₂ N₂ OΩ1.8H₂ O: C, 44.39; H,7.32; N, 9.41. Found: C, 44.55; H, 7.69; N, 9.32.

EXAMPLE 31

3-(1-methyl-2-(S)-pyrrolidinylmethoxy)quinoline hydrochloride

To (S)-1-methyl-2-pyrrolidinylmethanol (1.07 mL, 9.0 mmol) and3-bromoquinoline (1.46 mL, 10.8 mmol) was added triphenylphosphine (472mg, 1.8 mmol), CuBr (129 mg, 0.9 mmol) and K₂ CO₃ (1.19 g, 9 mmol), andthe reaction mixture was heated to 100° C. for 16 hours. The reactionmixture was then quenched with 10% aq. HCl, and the aqueous layer waswashed with methylene chloride (4×15 mL). The aqueous layer was adjustedto approx. pH 14 with K₂ CO3 (solid) and extracted with methylenechloride (2×30 mL). The organic extracts were dried (MgSO₄) andconcentrated to afford the crude product as an oil. Chromatographicpurification (silica, MeOH(CHCl₃) afforded the product as a free base(571 mg, 26%), which was converted to the hydrochloride salt in a mannersimilar to Example 1b, using ether instead of ethanol. MS(DCI/NH₃) m/e:243 (M+H)⁺ ; ¹ H-NMR (D₂ O) δ: 8.79 (d, 1H), 8.14 (d, 1H), 8.09-8.0 (m,2H), 7.86-7.73 (m, 2H), 4.67 (dd, 1H), 4.50 (dd, 1H), 4.02 (m, 1H), 3.80(m, 1H), 3.30 (m, 1H), 3.10 (s, 3H), 2.53-2.38 (m, 1H), 2.30-2.09 (m,2H). Anal. Calc for C₁₅ H₁₈ N₂ OΩ2HCl: C, 57.15; H, 6.39; N, 8.89;Found: C, 57.14; H, 6.35; N, 8.90.

EXAMPLE 32

4-(1-methyl-2-(S)-pyrrolidinylmethoxy)isoquinoline hydrochloride

To (S)-1-methyl-2-pyrrolidinyl methanol (1.07 mL, 9.0 mmol) and4-bromoisoquinoline (2.24 g, 10.8 mmol) was added triphenylphosphine(472 mg, 1.8 mmol), CuBr (129 mg, 0.9 mmol) and K₂ CO₃ (1.19 g, 9 mmol),and the reaction mixture was heated to 100° C. for 16 hours. Thereaction mixture was then quenched with 10% aq. HCl and the aqueouslayer was washed with methylene chloride (4×15 mL). The aqueous layerwas then adjusted to approx. pH 14 with K₂ C₃ (solid) and extracted withmethylene chloride (2×30 mL). The organic extracts were dried (MgSO₄)and concentrated to afford the crude product as an oil. Chromatographicpurification (silica, MeOH/CHCl₃) gave the product as a free base (216mg, 10%), which was converted to the hydrochloride salt in a mannersimilar to Example 1b, using ether instead of ethanol. MS(DCI/NH₃) m/e:243 (M+H)⁺ ; ¹ H-NMR (D₂ O) δ: 9.33 (s, 1H), 8.50-8.42 (m, 2H),8.25-8.18 (m, 2H), 8.11-8.03 (m, 1H), 4.96-4.72 (m, 2H; partially buriedunder H₂ 0 peak), 4.16 (m, 1H), 3.84 (m, 1H), 3.25 (m, 1H), 3.17 (s,3H), 2.57-2.46 (m, 1H), 2.36-2.16 (m, 2H Anal. Calc for C₁₅ H₁₈ N₂ OΩ0.5H₂ OΩ2HCl: C, 55.56; H, 6.53; N, 8.64; Found: C, 55.63; H, 6.28; N,8.50.

EXAMPLE 33

5-chloro-3-(2-(R)-pyrrolidinylmethoxy)pyridine dihydrochloride

33a. (R)-1-t-butoxycarbonyl-2-pyrrolidinemethanol

N-t-BOC-(R)-proline was treated as in Example 15a. The resultingmaterial was carried on without any further purification.

33b. 5-chloro-3-(N-t-butoxycarbonyl-2-(R)-pyrrolidinylmethoxy)pyridine

Starting with the material from step 33a, and following the procedure ofExample 15b, the title compound was prepared. TLC R_(f) 0.75 (1:1EtOAc/Hex). MS (DCI/NH₃) m/e: 313 (M+H)⁺ with ³⁵ Cl and m/e: 315 (M+H)⁺with ³⁷ Cl.

33c. 5 chloro-3-(2-(R)-pyrrolidinylmethoxy)pyridine dihydrochloride

The product of Example 33b was treated according to the procedures ofExamples 2b and 1b to give the title product. The MS and ¹ H NMR (D₂ O,300 MHz) were similar to Example 15d. Anal. Calc. for C₁₀ H₁₃ N₂OClΩ2.00 HCl: C, 42.06; H, 5.29; N, 9.81; Found C, 42.91; H, 5.44; N,9.86. α!_(D) ²⁵ =-11.15° (c=1, MeOH).

EXAMPLE 34

5-chloro-3-((1-methyl-2-(R)-pyrrolidinyl)methoxypyridine dihydrochloride

34a. 5-chloro-3-((1-methyl-2-(R)-pyrrolidinylmethoxypyridine.

Following the procedure of Example 16a, replacing the5-chloro-3-(N-t-butoxycarbonyl-2-(S)-pyrrolidinylmethoxy)pyridinethereof with5chloro-3-(N-t-butoxycarbonyl-2-(R)-pyrrolidinylmethoxy)pyridine(prepared from the (R)-isomer of the starting material following theprocedure of Example 15a), the title compound was prepared. TLC R_(f)=0.23 (10%MeOH/CHCl₃). MS and ¹ H NMR (CDCl₃, 300 MHz) are similar to16a.

34b. 5chloro-3-((1-methyl-(R)-pyrrolidinyl)methoxy pyradinedihydrochloride

The compound of step 34a was treated with HCl as described in Example 1band the title compound was isolated as a white powder. MS and ¹ H NMR(D₂ O, 300 Hz) are similar to 16b. Anal. Calc for C₁₁ H₁₅ N₂ OClΩ2.00HCl: C, 44.10; H, 5.20; N, 9.35; Found C, 43.98; H, 5.81; N, 9.33.α!_(D) ²⁵ =+5.59 ° (c=1, MeOH).

EXAMPLE 35

2-methyl-3-(2-(R)-pyrrolidinylmethoxy)pyridine dihydrochloride

35a. 2-methyl-3-(2-(R)-pyrrolidinylmethoxypyridine

Replacing (S)-1-t-butoxycarbonyl-2-pyrrolidinemethanol of Example 15with (R)-1-t-butoxycarbonyl-2-pyrrolidinemethanol (Aldrich ChemicalCo.), and following the procedure of steps 15a and 15b, the titlecompound was prepared. The MS and ¹ H NMR spectra were similar tocompound 15a.

35b. 2-methyl-3-(2-(R)-pyrrolidinylmethoxypyridine dihydrochloride

The compound of step 35a was treated with HCl and isolated as describedin Example 1b to give a white powder. MS and ¹ H NMR (D₂ O,300 Hz) aresimilar to 17b. Anal. Calc for C₁₁ H₁₆ N₂ OΩ2.00 HCl: C, 48.82; H, 6.84;N, 10.56; Found C, 49.55; H, 6.95; N, 10.52. α!_(D) ²⁵ =-27.01° (c=1,MeOH).

EXAMPLE 36

6methyl-3-((1-methyl-2-(R)-pyrrolidinyl)methoxypyridine dihydrochloride

36a. 6-methyl-3-((I-t-butoxycarbonyl-2-(R)-pyrrolidinyl)methoxy)pyridine

Replacing the6-methyl-3-(1-t-butoxycarbonyl-2-(S)-pyrrolidinylmethoxy)pyridine ofExample 18b with6-methyl-3-(1-t-butoxycarbonyl-2-(R)-pyrrolidinylmethoxy)pyridine(prepared from (R)-1-t-butoxycarbonyl-2-pyrrolidinemethanol (AldrichChemical Co.) by the procedure described in step 18a), the titlecompound was prepared by a procedure similar to that of step 18b. TLCR_(f) =0.42 (1:1 ethyl acetate/hexane).

36b. 6methyl-3-((1-methyl-2-(R)-pyrrolidinyl)methoxy)pyridine

The title compound was prepared from the compound of step 36a in amanner similar to compound 18b TLC R_(f) =0.17 (10%MeOHI/CHCl₃). MS(DCI/NH₃) and ¹ H NMR (CDCl₃,300 MHz) are similar to the compound ofstep 18b

36c. 6-methyl-3-((1-methyl-2-(R)-pyrrolidinyl)methoxy)pyridinedihydrochloride

The compound of step 36b was treated with HCl as described in Example1b, and the title compound was isolated as a white powder. The MS and ¹H NMR spectra were similar to the compound of 18c. Anal. Calc for C₁₂H₁₈ N₂ OΩ2.00 HCl: C, 51.62; H, 7.22; N,10.03; Found C, 51.36; H, 7.53;N, 9.93. α!_(D) ²⁵⁼⁺ 6.22° (c=1, MeOH).

EXAMPLE 37

6methyl-3-(2-(R-pyrrolidinylmethoxy)pyridine dihydrochloride

The compound of Example 35a was treated according to the proceduresdescribed in Examples 17a and 17b to give the title compound as a whitepowder. The MS and ¹ H NMR spectra were similar to the compound of 17b.Analysis calculated for C₁₁ H₁₆ N₂ OΩ2.00 HCl: C, 49.82; H, 6.84; N,10.56; Found C, 49.89; H, 6.59; N, 10.33. α!_(D) ²⁵ =-10.47° (c=1,MeOH).

EXAMPLE 38

3-((1-ethyl-2(S)-pyrrolidinyl)methoxy)pyridine dihydrochloride

38a. 3-((1-ethyl-2-oxo5-(S)-pyrrolidinyl)methoxy pyridine

To a solution of the compound from Example 22a (1.50 g, 7.8 mmol) inanhydrous THF at 0° C. was added NaH (60% yield dispersion, 0.625 g,15.6 mmol) was added, and the reaction mixture was stirred for 20minutes at this temperature. The reaction was then warmed to roomtemperature, and iodoethane (1.25 mL, 15.6 mmol) was added via syringe.After starting material was consumed, NaHCO₃ was added to the reactionfollowed by CHCl₃. The desired compound was extracted from the aqueousphase, and the organic layer was subjected to a brine wash (2×). Theorganic layer was dried over MgSO₄. The residue was purified by silicagel flash chromatography (5% yield MeOH/CHCl₃) to give 0.23 g (13%yield) of the title compound as an oil. MS (DCI/NH₃) m/e 221 (M+H)⁺ and238 (M+NH₄ ⁺)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ: 8.39-8.33 (m, 1H), 8.33-8.28(m, 1H), 7.39-734 (m, 2H), 4.20-4.00 (m, 3H), 3.78-3.64 (m, 1H),3.22-3.07 (m, 1H), 2.63-2.49 (m, 1H), 2.47-2.23 (m, 2H), 2.06-1.91 (m,1H).

38b. 3-((1-ethyl-2-(S)-pyrrolidinyl)methoxy)pyridine

To the compound of step 38a (222 mg, 1.01 mmol) in 3 mL of THF wasadded, under nitrogen and dropwise over a period of 5 minutes, 3.03 mL(3.03 mmol) of a 1 M solution of borane in THF. After stirring underreflux for 3 hours, methanol was added dropwise, and the reaction wasstirred for an additional 30 minutes. The solvent was removed in vacuo,affording a white solid borane complex. This solid was dissolved inanhydrous ethanol. Cesium fluoride (0.347 g, 3.03 mmol) was added, andthe resultant solution was stirred under reflux for 16 hr. Evaporationof the solvent provided a white solid which was purified on a silica gelcolumn, eluting with chloroform:methanol (10:1) to give 162 mg of thedesired methyl compound as an oil in 78% yield. MS (DCI/NH₃) m/e 207(M+H)+. ¹ H NMR (CDCl₃, 300 MHz) δ: 8.36-8.31 (m, 1H), 8.28-8.21 (m,1H), 7.26-7.20 (m, 2H), 4.30-4.10 (m 1H), 4.02-3.90 (m, 1H), 3.43-3.23(m, 1H), 3.20-2.90 (m, 2H), 2.68-2.28 (m, 2H), 2.16-1.76 (m, 2H),1.72-1.44 (m, 1H).

38c. 3-((1-ethyl-2-(S)-pyrrolidinyl)methoxy)pyridine dihydrochloride

The free base from step 38b was dissolved in diethyl ether and broughtto 0° C. with stirring. The solution was treated with diethyl ethersaturated with HCl. The solvent was removed in vacuo. The resulting saltwas triturated with diethyl ether (2×) and dried under vacuum to give awhite powder. MS (DCI/NH₃) m/e207 (M+H)⁺. ¹ H NMR (D₂ O,300 MHz) δ: 8.49(d, J=3.0 Hz, 1H), 8.39 (dd, J=1.0,5.1 Hz, 1H), 8.02 (m, 1H), 7.85 (dd,J=8.70, 5.40 Hz, 1H), 4.61 (dd, J=11.0, 3.3 Hz, 1H), 4.44 (dd, J=11.0,6.6 Hz, 1H), 4.10-4.01 (m, 1H), 3.79-3.72 (m, 1H), 3.65-3.51 (m, 2H),3.32-3.18 (m, 2H), 2.44-2.33 (m, 1H), 2.27-2.05 (m, 2H), 1.37 (t, J=7.5Hz, 3H). Anal. Calc. for C₁₂ H₁₈ N₂ OΩ2.0 HCl: C, 51.57; H, 7.16; N,10.02; Found C, 51.43; H, 7.39; N, 9.96. α!_(D) =-1.5° (c 0.46, MeOH).

EXAMPLE 39

5-chloro-3-(2-(S)-azetidinylmethoxy)pyridine dihydrochloride

39a. 5-chloro-3-(N-t-butoxycarbonyl-2-(S)-azetidinylmethoxy)pyridine

An ice-cooled solution of the compound from Example 7b (0.242 g, 1.20mmol) was allowed to react with 3-chloro-5-hydroxypyridine (0.187 g,1.40 mmol) under the conditions of Example 2a, except that DEAD wasreplaced with di-t-butylazodicarbonate, to yield the title compound(0.137 g, 88%o) after purification on silica gel (ethyl acetate/hexane2:1). MS (DCI/NH₃) m/e: 299 (M+H)⁺. ¹ H NMR (CDCl₃,300 MHz) δ: 8.25 (d,J=1.38 Hz, 1H), 8.21 (br. s, 1H), 7.29 (t, J=2.2 Hz, 1H), 4.53-4.51 (m,1H), 4.34-4.33 (m, 1H), 4.13 (dd, J=10.3, 2.9 Hz, 1H), 3.91-3.86 (m,2H), 2.51 (s, 3H), 2.38-2.29 (m, 2H), 1.43 (s, 9H).

39b. 5-chloro-3-(2-(S)-azetidinylmethoxy)pyridine dihydrochloride

The compound from step 39a (0.130 g, 0.44 mmol) was treated withsaturated ethanolic HCl (5 mL) for 16 hr. The volatiles were removed invacuo, and the dihydrochloride was recrystallized (EtOH/Et₂ O) to yieldthe title compound (0.094 g, 80%) as a white solid. mp 156-157° C. MS(DCI/NH₃) m/e: 199 (M+H)⁺, 216 (M+NH₄)⁺. ¹ H NMR (D₂ O, 300 MHz) δ: 8.41(d, J=5.1 Hz, 1H), 8.39 (d, J=4.4 Hz, 1H), 7.94 (t, J=2.1 Hz, 1H),5.01-4.93 (m, 1H), 4.50 (d, J=4.0 Hz, 2H), 4.20-4.03 (m, 2H), 2.69 (q,J=8.45 Hz, 2H). Anal. calc. for C₉ H₁₃ Cl3N₂ O•0.5H₂ O: C, 38.53; H,5.03; N, 9.98 Found: C, 38.51; H, 5.16 N, 9.96. α!_(D) ²³ =-3.23°(c=0.16 in MeOH).

EXAMPLE 40 6methyl-3-(2-(S)-azetidinylmethoxy)pyridine dihydrochloride

40a. 6-methyl-3-(N-t-Butoxycarbonyl-2-(S)-azetidinylmethoxy pyridine

An ice cooled solution of the compound from Example 7b (0.232 g, 1.24mmol) was allowed to react with 3-hydroxy-2-methylpyridine (Aldrich,0.142 g, 130 mmol) under the conditions of Example 2a, except that DEADwas replaced with di-t-butylazodicarbonate to yield the title compound(0.123 g, 36%) after purification on silica gel (ethyl acetate/hexane2:1). MS (DCI/NH₃) m/e: 279 (M+H)⁺. ¹ H NMR (CDCl₃,300 MHz) δ: 8.23-8.22(d, J=2.6 Hz, 1H), 7.20 (dd, J=8.5, 3.0 Hz, 1H), 7.08 (d, J=8.5 Hz, 1H),4.51-4.49 (m, 1H), 430-4.28 (m, 1H), 4.13 (dd, J=9.9 ,2.9 Hz, 1H), 3.89(t, J=7.75 Hz, 2H), 2.51 (s, 3H), 2.37-2.28 (m, 2H), 1.41 (s, 9H).

40b. 6-methyl-3-(2-(S)-azetidinylmethoxy)pyridine dihydrochloride

The compound from step 40a (0.123 g, 0.44 mmol) was treated withsaturated ethanolic HCl (5 mL) for 18 hr. The volatiles were removed invacuo, and the dihydrochloride was washed with Et₂ O (3×20 mL),evaporated to dryness and recrystallized (EtOH/Et₂ O) to yield the titlecompound (0.074 g, 63%) as a white solid. mp 141-144° C. MS (DCI/NH₃)m/e: 179 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ: 8.33 (d, J=2.9 Hz, 1H), 7.89(dd, J=9.0, 2.8 Hz, 1H), 7.64 (d J=8.8 Hz, 1H), 5.01-4.93 (m, 1H), 4.48(d, J=4.4 Hz, 2H), 4.21-4.04 (m, 2H), 2.70 (q, J=8.5 Hz, 2H), 2.62 (s,3H). Anal. calc. for C₁₀ H₁₆ Cl₂ N₂ O•1.0H₂ O: C, 44.62; H, 6.74; N,10.41. Found: C, 44.55; H, 7.02; N, 10.50. α!^(D) ₂₄ -7.89° (c=0.19 inMeOH).

EXAMPLE 41 2-methyl-3-(2-(R)-azetidinylmethoxy)pyridine dihydrochloride

41a. 1-t-butoxycarbonyl-2-(R)-hydroxymethyiazetidine

An ice cooled solution of 2-(R)-azetidine carboxylic acid (0.400 g, 3.96mmol, preparation as described by Miyoshi et al., Chemistry Lett., 1973:5) was allowed to react under the conditions described in Example 7a toyield the protected acid (0.237 g, 30%) which was used without furtherpurification. This crude product was allowed to reaction under theconditions described in Example 7b to yield the title compound, whichwas used without further purification. MS (CDI/NH₃) m/e: 188 (M+H)⁺, 205(M+NH₄)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ: 4.46-4.42 (m, 1H), 3.92-3.69 (m,2H), 2.21-2.12 (m, 2H), 1.99-1.87 (m, 2H).

41b. 2-methyl-3-(N-t-butoxycarbonyl-2-(R)-azetidinylmethoxy)pyridine

An ice cooled solution of the compound from step 41a (0.151 g,0.81 mmol)was allowed to react with 2-methyl-3-hydroxypyridine (0.092 g, 0.85mmol) under the conditions of Example 2a, except that DEAD was replacedby di-t-butyl azodicarbonate, to yield the title compound (0.125 g,55%). MS (DCI/NH₃) m/e: 279 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ: 8.11(dd, J=4.6, 1.3 Hz, 1H), 7.20-7.10 (m, 2H), 4.54-4.53 (m, 1H), 4.36-435(m, 1H), 4.09 (dd, J=10.0, 2.6 Hz, 1H), 3.95-3.88 (m, 2H), 2.55 (s, 3H),2.42-2.30 (m, 2H), 1.40 (s, 9H).

41c. 2-methyl-3-(2-(R)-azetidinylmethoxy)pyridine dihydrochloride

The compound from step 41b (0.121 g, 0.435 mmol) was treated withsaturated ethanolic HCl (5 mL). After 16 hr, the volatiles were removedin vacuo, and the dihydrochloride was recrystallized (EtOH/Et₂ O) toyield the title compound (0.098 g, 90%) as a hygroscopic oil. MS(DCI/NH₃) m/e: 179 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ: 8.16 (d, J=5.5 Hz,1H), 7.79 (d, J=8.5 Hz, 1H), 7.62 (dd, J=8.5, 5.5 Hz, 1H), 5.00 (m, 1H),4.57-4.47 (m, 2H), 4.24-4.12 (m, 2H), 2.78-2.71 (m, 2H). Anal. calc. forC₁₀ H₁₆ CIN₂ O•0.5H₂ O: C, 46.17 H, 6.59 N, 10.77. Found: C, 45.93; H,6.61 N, 10.63. α!_(D) ²³ -5.85° (c=0.21 in MeOH).

EXAMPLE 42 3-((1-methyl-2-(R)-piperidinyl)methoxy)pyridinedihydrochloride

42a. (R)-N-(t-butyloxycarbonyl)pipecolinic acid

A 10.44 g (80.9 mmol) sample of (R)-pipecolinic acid, previouslyresolved according to Hemingway, R. J., J. Pharm. Pharmac., 20, 87-91,(1968), was dissolved in 70 mL of dioxane and 40 mL of H₂ O, and 40 mLof 1M K₂ CO₃ and 39 mL of di-t-butyldicarbonate were added. The reactionwas stirred at room temperature for 16 hr, then an additional 10 mL ofdi-t-butyldicarbonate and 40 mL of 1M K₂ CO₃ were added and the reactioncontinued for another 24 hr. The solvents were removed on a rotaryevaporator, 10% citric acid solution was added to the residue, and themixture was extracted with CHCl₃. The extract was dried over MgSO₄,filtered and concentrated to give the title product as a white solid.MS: 247 (M+NH₄)⁺, 230 (M+H)⁺, 191 (M-C₄ H₈ +NH₄)⁺.

42b. 1-methyl-2-(R)-hydroxymethylpiperidine

To the compound from step 42a (1.06 g, 4.63 mmol) in anhydrous THF (10mL) under N₂ at 0° C. was added LiAlH₄ (1M in diethyl ether; 15 mL). Thereaction was stirred for 16 hr, and additional LiAlH₄ (8 mL) was added.The reaction was quenched by the addition of sodium sulfate decahydrate(60 mg), filtered through celite and washed with THF. The combinedorganics were concentrated in vacuo to yield the title compound as anoil (0.552 g, 93%). This material was carried forward without furtherpurification. MS (CDI/NH₃) m/e: 130 (M+H)⁺. 1H NMR (CDCL₃, 300 MHz) δ:3.86 (dd, 1H), 3.41 (dd, 1H), 2.88 (m, 1H), 2.32 (s, 3H), 2.18 (m, 2H),1.98 (m, 1H), 1.76 (m, 1H), 1.62 (m, 2H), 1.51 (m, 1H), 1.29 (m, 1H).

42c. 3-((1-methyl-2-(R)-piperidinyl)methoxy)pyridine dihydrochloride

The compound from step 42b (553 mg, 4.28 mmol) was allowed to react with3-bromopyridine (0.43 mL, 4.50 mmol), cuprous bromide (0.165 g, 0.86mmol), triphenylphosphine (0.449 g, 1.7 mmol) and potassium carbonate(0.592 g, 4.28 mmol). The reaction mixture was heated to 90° C. andstirred for 120 hr, then cooled to 25° C., acidified with HCl (1.5M; 35mL) and washed with ethyl acetate (4×50 mL). The aqueous layer wasbasified with saturated aqueous potassium carbonate, and the product wasextracted with chloroform (6×50 mL), dried (MgSO₄) and concentrated invacuo to an oil. The crude product was purified by chromatography onsilica gel (CH₂ Cl₂ /EtOAc/MeOH/NH₄ OH 50:50:4:1) to yield the free baseof the title compound (0.048 g). The amine was treated as in example 1bto yield the title compound as a hygroscopic semisolid (0.024 g, 2%). MS(DCI/NH₃) m/e: 207 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ:8.37-8.29 (m, 2H),7.66 (dd, J=8.45, 1.5 Hz, 1H), 7.59-7.57 (m, 1H), 4.63 (dt, J=14.5, 2.4Hz, 2H), 4.8 (dd, J=11.9, 1.8 Hz, 1H), 3.58-3.53 (m, 2H), 3.20 (m, 1H),2.93 (s, 3H), 2.05-1.60 (m, 5H). Anal. calc. for C₁₂ H₂₀ Cl₂ N₂ O•2.0 H₂O: C, 45.72; H, 7.67; N, 8.89. Found: C, 45.82; H, 7.93; N, 8.84. α!_(D)²³ -1.14° (c=0.71 in MeOH).

EXAMPLE 43 2-chloro-3-(2-(S)-pyrrolidinylmethoxy)pyridinedihydrochloride

43a. 2-chloro-3-(2-(S)-pyrrolidinylmethoxy)pyridine

(S)-1-t-Butoxycarbonyl-2-pyrrolidinemethanol (2.01 g, 10.0 mmol,prepared in Example 15a) and 5-chloro-3-pyridinol (1.454 g, 11.0 mmol,Aldrich Chemical Co.). were allowed to react in the presence oftriphenylphosphine and DEAD as described in Example 2a. The crudeproduct was hydrolyzed with 10% HCl at room temperature for 0.5 hours.The solution was made basic with NaHCO₃, then extracted with ethylacetate. After removal of the solvent, the residue was purified bychromatography over silica gel to give 166.5 mg of the title product. MS(DCI/NH₃) m/e: 213 (M+H)⁺ and 215 (M+H)⁺. ¹ H NMR (CDCl₃, 300MHz) δ:7.99 (d, J=5.1 Hz, 1H), 7.25 (d, J=8.5 Hz, 1H), 7.20 (dd, J=5.1, 8.5Hz), 1H), 4.08-4.01 (m, 1H), 4.40-3.94 (m, 1H), 3.69-3.58 (m, 1H),3.15-2.98 (m, 2H), 2.07-1.61 (m, 4H).

43b. 2-chloro-3-(2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

The compound from step 43a was treated with HCl and the product isolatedas described in Example 1b, affording 155 mg of the title compound. mp203-205° C. MS (DCI/NH₃) m/e: 213 (M+H)⁺ and 215 (M +H)⁺. ¹ H NMR (D₂ O,300 MHz) δ: 8.00 (d, J=5.1 Hz, 1H), 7.56 (d, J=8.5 Hz, 1H), 7.43 (dd,J=5.1 Hz, 1H), 4.58-4.50 (m, 1H), 4.32-4.24 (m, 1H), 4.24-4.12 (m, 1H),3.51-3.37 (m, 2H), 2.37-1.95 (m, 4H). Anal. Calc. for C₁₀ H₁₃ N₂OCl•2.00 HCl: C, 42.06; H, 5.29; N, 9.81; Found C, 42.28; H, 4.95; N,10.02. α!_(D) ²⁵ =+18.3° (c=1.01, MeOH).

EXAMPLE 443-(1-methyl-2-(S)-pyrrolidinylmethoxy)-5-trifluoromethylpyridinedihydrochloride

44a. 3-(-1-methyl-2-(S)-pyrrolidinylmethoxy)-5-trifluoromethylpyridine

(S)-(-)-1-Methyl-2-pyrrolidinemethanol (Aldrich Chemical Co., 0.5 g,4.34 mmol) was reacted with 3-chloro-5-trifluoromethylpyridine accordingto the method of Example 3, except using DMF in place of THF as solventand reducing reaction time to less than 2 hours. The solvent wasremoved, the residue dissolved in ethyl acetate, and the productpurified by chromatography over silica gel to give 170 mg of the titlecompound. MS (DCI/NH₃) m/e: 261 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ: 8.50(d, J=0.6 Hz, 1H), 8.49 (d, J=3.0 Hz, 1H), 7.41 (dd, J=0.6 Hz, 1H), 8.49(d, J=3.0 Hz, 1H), 7.41 (dd, J=0.6, 3.0 Hz, 1H), 4.12-3.96 (m, 2H),3.21-3.10 (m, 1H), 2.80-2.65 (m, 1H), 2.51 (s, 3H), 2.44 (m, 1H),2.14-1.73 (m, 4H).

44b. 3-(1-methyl-2-(S)-pyrrolidinylmethoxy)-5-trifluoromethylpyridinedihydrochloride

The compound from step 43a was treated with HCl and the product isolatedas described in Example 1b, affording the title compound. mp 243-246° C.MS (DCI/NH₃) m/e: 261 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ: 8.58 (d, J=0.6Hz, 1H), 8.55 (d, J=3.0 Hz, 1H), 7.82 (dd, J=0.6, 3.0 Hz, 1H), 4.60 (dd,J=11, 2.9 Hz, 1H), 4.43 (dd, J=10.6, 6.2 Hz, 1H), 4.05-3.93 (m, 1H),3.82-3.72 (m, 1H), 3.37-3.22 (m, 1H), 3.06 (s, 3H), 2.49-2.05 (m, 4H).Anal. Calc. for C₁₂ H₁₆ N₂ OF₃ Cl•0.50 H₂ O: C, 45.76; H, 5.28; N, 8.89;Found C, 45.51; H, 5.25; N, 9.16. α!_(D) ²⁵ =-1.1° (c=0.57, MeOH).

EXAMPLE 45 3-(2-(S)-pyrolidinylmethoxy)-6-chloropyridine dihydrochloride

45a 3-(1-t-butoxycarbonyl-2-(S)-pyrrolidinylmethoxy-6-chloropyridine

A sample of (S)-1-t-butoxycarbonyl-2-pyrrolidinemethanol (1.12 g, 5.568mmol, prepared as in Example 15a above) and 600 mg (4.64 mmol) of2-chloro-5-hydroxypyridine were reacted with triphenylphosphine and DEAD(5.88 mmol each) in 20 mL of THF according to the procedure of Example14a MS (DCI/NH₃) m/e: 313/315 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) γ: 8.09(dd, J=2.1, 2.1 Hz, 1H), 7.24-7.19 (m, 2H), 4.23-4.05 (m, 2H), 4.03-3.83(m, 1H), 3.45-3.31 (m, 1H), 2.08-1.84 (m, 4H), 1.7 (s, 9H).

45b. 3-(2-(S)-pyrrolidinylmethoxy)-6-chloropyridine

The compound from step 45a was treated with TFA as in Example 14b toafford 140 mg of the title compound. MS (DCI/NH₃) m/e: 213/215 (M+H)⁺and 230/232 (M+NH₄)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ: 8.06 (d, J=3.0 Hz,1H), 7.28 (dd, J=8.8, 3.0 Hz, 1H), 7.23 (d, J=8.8 Hz, 1H), 414-4.10 (m,2H), 3.83-3.73 (m, 1H), 3.22-3.15 (m, 2H), 2.20-1.75 (m, 4H).

45c. 3-(2-(S)-pyrrolidinylmethoxy)-6-chloropyridine dihydrochloride

The compound from step 45b was treated with HCl in ether according toExample 14c to afford the title compound. mp 136-138° C. MS (DCI/NH₃)m/e: 213/215 (M+H)⁺ and 230/232 (M+NH₄)⁺. ¹ H NMR (D₂ O, 300 MHz) δ:8.13 (d, J=3.0 Hz, 1H), 7.52 (dd, J=8.8, 3.0 Hz, 1H), 7.45 (d, J=8.8 Hz,1H), 4.46 (dd, J=11.0, 3.0 Hz, 1H), 4.24 (dd, J=11.0, 5.8 Hz, 1H),4.17-4.06 (m, 1H), 3.46-3.27 (m, 2H), 2.35-1.90 (m, 4H). Anal. Calc. forC₁₀ H₁₅ N₂ OCl₃ : C, 42.06; H, 5.29; N, 9.81; Found C, 42.30; H, 4.96;N, 9.98. α!_(D) ²⁵ =+12.7° (c=0.60, MeOH).

EXAMPLE 46 4-methyl-3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridinedihydrochloride

46a. 4methyl-3-((1-methyl-2-(S)-pyrrolidinylmethoxy pyridine

To a 330 mg sample of 4methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine(from Example 27 above) was added a solution of formic acid/formaldehyde (1:2,2 mL). The mixture was heated at reflux for 5 hours,and the volatiles were removed by evaporation. The residue was dissolvedin 1 mL of 20% NaOH. The solution was extracted with CH₂ Cl₂ (3X), thenthe organic layer was dried (Na₂ SO₄) and concentrated. The crudeproduct was purified by chromatography over silica gel to afford 295 mgof the title compound. MS (DCI/NH₃) m/e: 207 (M+H)⁺. ¹ H NMR (CDCl₃, 300MHz) δ: 8.17 (s, 1H), 8.12 (d, J=5.5 Hz, 1H), 7.06 (d, J=5.5 Hz, 1H),4.07 (dd, J=3.3, 10.6 Hz, 1H), 3.98 (dd, J=7.4, 10.6 Hz, 1H), 3.15-3.08(m, 1H), 2.76-2.68 (m, 1H), 2.53 (s, 3H), 2.38-2.25 (m, 1H), 2.26 (s,3H), 2.12-1.67 (m, 4H).

46a. 4methyl-3-(1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridinedihydrochloride

The compound from step 46b was treated with HCl in ether according toExample 14c to afford the title compound. mp 217-21920 C. MS (DCI/NH₃)m/e: 207 (M+H)⁺. ¹ -H NMR (D₂ O, 300 MHz) δ: 8.34 (s, 1H), 8.32 (d,J=5.5 Hz, 1H), 7.76 (d, J=5.5 Hz, 1H), 4.65 (dd, J=3.3, 10.6 Hz, 1H),4.44 (dd, J=7.4, 10.6 Hz, 1H), 4.08-4.00 (m, 1H), 3.83-3.77 (m, 1H),3.33-3.22 (m, 1H), 3.10 (s, 3H), 2.49 (s, 3H), 2.50-2.06 (m, 4H). Anal.Calc. for C₁₂ H₂₀ N₂ OCl₂ : C, 51.62; H, 7.22; N, 10.03; Found C, 51.60;H, 7.02; N, 9.74. α!_(D) ²⁵ =+6.3o (c=1.80, MeOH).

EXAMPLE 47

3-((trans-4-methoxy-1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridinedihydrochloride

47a. 3-((trans-1-Methyl-4-methoxy-5-oxo-2(S)-pyrrolidinyl)methoxypyridine

A 250 mg (1.13 mmol) sample of3-(trans-1-methyl-4-hydroxy-5-oxo-2(S)-pyrrolidinylmethoxy)pyridine(from Example 23a) was dissolved in 5 mL of anhydrous THF and brought to0° C. NaH ((80% dispersion in mineral oil), 90 mg, 2.26 mmol) was addedand the reaction mixture was allowed to warm to room temperature withstirring. After stirring at room temperature for 30 minutes methyliodide (0.178 mL) and tetrabutylammonium iodide were added, and thereaction mixture was stirred for 16 hours. The reaction was quenched bythe addition of water, and the mixture was extracted with chloroform.The extract was dried over MgSO₄, filtered and concentrated. The solventwas removed, and the residue was purified by column chromatography onsilica gel, eluting with 10: 1 chloroform:methanol to afford 242 mg ofthe title compound.

47b. 3-((4-methoxy-1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine

To the compound from step 47a above, dissolved in 4 mL of THF, was added3.39 mL of BH₃ and the mixture was heated at reflux for 2 hours.Methanol was added to the reaction mixture and evaporated. The residuewas dissolved in anhydrous ethanol. Cesium fluoride was added, and theresultant solution was stirred under reflux for 16 hr. Evaporation ofthe solvent provided a white solid which was purified on a silica gelcolumn. MS (DCI/NH₃) m/e: 223 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ: 8.34(m, 1H), 8.23 (t, J=3 Hz, 1H), 7.22 (m, 1H), 3.93-4.10 (m, 3H),3.44-3.54 (m, 1H), 3.32 (s, 3H), 3.03-2.87 (m, IF), 2.51 (s, 3H),2.44-2.33 (m, 11H), 2.11-1.92 (m, 2H).

47c. 3-((4methoxy-1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridinedihydrochloride

The compound from step 47b was treated with HCl in ether according toExample 14c to afford the title compound. MS (DCI/NH₃) m/e: 223 (M+H)⁺.¹ H NMR (D₂ O, 300 MHz) δ: 8.61 (m, 1H), 8.43 (d, 1H, J=5.32 Hz), 7.91(m, 1H), 7.74 dd, 1H, J=5.34, 8.1 Hz), 4.61-4.53 (m, 2H), 4.14 (m, 1H),3.98 (m, 1H), 3.81 (m, 1H), 3.30 (s, 3H), 3.22 (m, 1H), 2.96 (s, 3H),2.37 (m, 1H), 2.01 (m, 1H). Anal. Calc. for C₁₂ H₂₀ N₂ O₂ Cl₂ : C,48.82; H, 6.82; N, 9.49; Found C, 48.56; H, 6.88; N, 9.43.

EXAMPLE 483-((cis-hydroxymethyl-1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridinedihydrochloride

48a. 3-(1-methyl-4-hydroxmethyl-5oxo-2(S)-pyrrolidinylmethoxy)pyridine

A 4.12 g (20 mmol) sample of3-((1-methyl-5-oxo-2-(S)-pyrrolidinyl)methoxy)pyridine, from Example 22babove, was dissolved in 50 mL of dry THF and cooled to -7820 C. To thissolution was added 14.67 mL (22 mmol) of LDA, and the mixture wasstirred for 1 hour. The temperature of the reaction mixture was warmedto -2020 C. to -1020 C., and 4 g (200 mmol) of paraformaldehyde wasadded. The reaction was stirred at this temperature for 3 hours. Thereaction was quenched by addition of H₂ O, and the mixture was taken todryness. The residue was repeatedly triturated with ethyl acetate todissolve the product The solvent was removed, and the resdiue waspurified on a silica gel column, eluting with 100:) to 100: 10 CHCl₃:methanol, to afford 2.90 g of the title compound.

48b. 3-((4-hydroxymethyl-1-methyl-2-(S)-pyrrolidinyl)methoxy pyridine

A 401 mg (2 mmol) sample of3-(1-methyl-4-hydroxymethyl-5-oxo-2(S)-pyrrolidinylmethoxy)pyridine,from step 48a above, was dissolved in 6 mL of THF and 6 mL of 1M B₂ H₆was added. The reaction mixture was heated at reflux for 2 hours, thenstirred at room temperature for 15 minutes after methanol was added. Thesolvent was removed under pressure, and the residue was dissolved in 4mL of ethanol. The this solution was added 251 mg of CsF, and thereaction mixture was heated at reflux for 16 hours. The solvent wasremoved, and the residue was purified on a column of silica gel, elutingwith 100:5 to 10: 1 chloroform:methanol 78 mg of a mixture of cis andtrans product.

cis compounδ: MS (DCI/NH₃) m/e: 223 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ:8.32 (m, 1H), 8.23 (t, 1H, J=3 Hz), 7.21 (m, 1H), 4.16-3.94 (m, 2H),3.77-3.54 (m, 2H), 3.09-3.01 (m, 1H), 2.88-2.64 (m, if), 2.58-2.47 (m,11H), 2.46 (s, 1H), 2.38-2.29 (m, 1H), 1.98-1.81 (m, 1H). transcompounδ: MS (DCI/NH₃) m/e: 223 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ: 8.33(m, 1H), 8.23 (m, 1H), 7.23 (m, 1H), 4.20-3.96 (m, 2H), 3.74-3.59 (m,2H), 3.42-3.26 (m, 1H), 2.97-2.83 (m, 1H), 2.54 (s, 1H), 2.48-2.23 (m,1H), 2.04-1.80 (m, 1H).

48c.3-((cis-4-hydroxymethyl-1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridinedihydrochloride

The cis-compound from step 48b was treated with HCl in ether accordingto Example 14c to afford the title compound. MS (DCI/NH₃) m/e: 223(M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ: 8.49 (d, 1H, J=3 Hz), 8.39 (dd, 1H,J=1, 5 Hz), 8.0 (m, 1H), 7.82 (dd, 1H, J=5, 8 Hz), 4.68-4.60 (m, 1H),4.54-4.43 (m, 1H), 4.10-3.95 (m, 1H), 3.76-3.60 (m, 2H), 3.50-3.40 (m,1H), 3.40 (s, 3H), 2.90-2.77 (m, 1H), 2.60-2.46 (m, 1H), 2.35-2.13 (m,1H), 1.98-1.85 (m, 1H). Anal. Calc. for C₁₂ H₂₀ N₂ O₂ CI₂ : C, 48.82; H,6.82; N, 9.49; Found C, 48.82; H, 6.68; N, 9.26.

EXAMPLE 493-((4methoxymethyl-1-methyl-2-(S)-pyrrolidinyl)methoxygpyridinedihydrochloride

49a.3-((4methoxymethyl-1-methyl-5-oxo-2-(S)-pyrrolidinyl)methoxy)-pyridine

A 327 mg (139 mmmol) sample of3-(1-methyl-4hydroxymethyl-5-oxo-2(S)-pyrrolidinylmethoxy)pyridine,prepared as in Example 48a above, was dissolved in 13 mL of anhydrousTHF, 111 mg (2.77 mmol) of NaH was added, and the mixture was stirredfor 30 minutes at room temperature. To this solution was added 258 mL(4.17 mmol) of methyl iodide and 256 mg of tetrabutylammomnum iodide,and the reaction was stirred at room temperature for 2 hours. Thereaction was quenched by the addition of water, and the mixture wasextracted with chloroform. The extract was dried over MgSO₄, filteredand concentrated. The solvent was removed, and the residue was purifiedby column chromatography on silica gel, eluting with 10: 1chloroform:methanol to give 314 mg of the title compound. MS (DCI/NH₃)m/e: 251 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ: 8.37-8.25 (m, 2H),7.35-7.25 (m, 2H), 4.18-4.0 (m, 2H), 3.99-3.84 (m, 1H), 3.73-3.58 (m,2H), 3.37 (s, 2H), 3.36 (s, 1H), 3.05 (s, 1H), 2.95 (s, 1H), 2.94 (s,1H), 2.90-2.63 (m, 1H), 2.49-2.24 (m, 2H).

49b. 3-((4-methoxymethyl-1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine

The compound from step 49a (314 mg) was dissolved in 3 mL of THF, 11.5mL of BH₃ was added, and the mixture was heated at reflux for 2 hours.The reaction was quenched by addition of methanol, and the mixture wasstirred for 30 minutes. The solvent was removed, and the solvent wasremoved, and the residue was purified by column chromatography on silicagel, eluting with 20: 1 chloroform:methanol. The purified intermediatewas dissolved in 4 mL of THF, 125 mg of BH₃ and 123 mg of CsF wereadded, and the reaction was heated at reflux for 2 hours. The solventwas removed, and the residue was purified by column chromatography onsilica gel, eluting with 1:10 chloroform:methanol to give 69 mg of thetitle compound. MS (DCI/NH₃) m/e: 236 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz)δ: 8.32 (m, 1H), 8.23 (t, J=3 Hz, 1H), 7.25-7.20 (m, 2H), 4.18-3.95 (m,2H), 3.30-3.48 (m, 3H), 3.36 (s, 3H), 3.13-3.03 (m, 1H), 2.70-2.40 (m,4H), 2.33-2.16 (m, 1H), 2.06-1.81 (m, 2H).

49c. 3-((4methoxymethyl-1-methyl-2-(S)-pyrrolidinyl)methoxypyridinedihydrochloride

The compound from step 49b was treated with HCl in ether according toExample 14c to afford the title compound. mp 158-160° C. MS (DCI/NH₃)m/e: 237 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ: 8.51 (d, 1H, J=2.9 Hz), 8.41(d, 1H, J=5.0 Hz), 8.05 (m, 1H), 7.87 (dd, 1H, J=5.2, 8.5 Hz), 4.64 (dd,1H, J-29, 11 Hz), 4.54-4.47 (m, 1H), 4.10-3.96 (m, 1H), 3.94-3.83 (m,1H), 3.70-3.46 (m, 2H), 3.39 (s, 3H), 3.06 (s, 2H), 3.04 (s, 1H),2.98-2.72 (m, 1H), 2.47-2.13 (m, 2H), 1.96-1.84 (m, 1H). Anal. Calc. forC₁₃ H₂₀ N₂ O₂ •1.8 HCl: C, 51.71; H, 7.28; N, 9.28; Found C, 51.70; H,7.14; N, 9.17.

EXAMPLE 503-((trans-4-cyanomethyl-1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridinedihydrochloride

50a.3-((trans-4-methanesulfonyloxmethyl-1-methyl-2-(S)-pyrrolidinyl)-methoxypyridine

To a 386 mg (1.84 mmol) sample of3-(trans-1-methyl-4-hydroxymethyl-2(S)-pyrrolidinylmethoxy)pyridine(from Example 48a above) dissolved in 12 mL of methylene chloride wereadded 262 μL (3.38 mmol) of methanesulfonyl chloride, 470 μL oftriethylamine and a catalytic amount of DMAP, and the reaction mixturewas stirred for 5 hours at room temperature. The reaction was quenchedwith water, the product extracted from the mixture, the solvent removed,and the product purified by column chromatography on silica gel, elutingwith 20:1 chloroform:methanol to afford 320 mg of the title compound.

50b.3-((trans-4-cyanomethyl-1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine

A 132 mg sample of the compound from step 50a above was dissolved 4 mLof a 6:1 solution of DMF:H₂ O, 240 mg of NaCN was added, and thereaction mixture was stirred at 95° C. for 16 hours. The solvent wasremoved, and the residue was purified by column chromatography on silicagel, eluting with 10:1 chloroform:methanol to afford 62 mg of the titlecompound. MS (DCI/NH₃) m/e: 232 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ: 8.34(m, 1H), 8.28 (m, 1H); 7.30-7.20 (m, 2H), 4.28-4.06 (m, 2H), 3.05-2.72(m, 5H), 2.65-2.52 (br s, 3H), 2.42-2.25 (m, 1H), 2.23-2.0 (m, 2H).

50c. 3-((trans-4-cyanomethyl-1-methyl-2-(S)-pyrrolidinyl)methoxypyridinedihydrochloride

The compound from step 50b was treated with HCl in ether according toExample 14c to afford the title compound. mp 203-205° C. MS (DCI/NH₃)m/e: 232 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ: 8.48 (d, 1H, J=3 Hz), 8.38(dd, 1H, J=1.0, 5.2 Hz), 7.96 (m, 1H), 7.80 (dd, 1H, J=5.1, 8.8 Hz),4.64 (dd, 1H, J=2.9, 11.4 Hz), 4.49 (dd, 1H, J=5.2, 11.1 Hz), 4.24-4.10(m, 1H), 4.05-3.91 (m, 1H), 3.09 (s, 3H), 3.25-3.02 (m, 2H), 3.0-2.8 (m,2H), 2.53-2.40 (m,-1H), 2.38-2.23 (m, 1H). Anal. Calc. for C₁₃ H₁₇ N₃O•1.7 HCl: C, 53.24; H, 6.43; N, 14.33; Found C, 53.21; H, 6.07; N,14.36.

EXAMPLE 51 3-((1-methyl-2-(R)-pyrrolidinyl)methoxy)-6-chloropyridinedihydrochloride

51a. 3-((1-methyl-2-(R)-pyrrolidinyl)methoxy)-6-chloropyridine

A 376 mg (1.2 mmol) sample of3-((1-t-butoxycarbonyl-2-(R)-pyrrolidinyl)methoxy)-6-chloropyridine,prepared from (R)-1-t-butoxycarbonyl-2-pyrrolidinemethanol by theprocedure described in Example 45a above, was treated withparaformaldehyde and formic acid for 2 hours as described in Example 16aabove. The crude material was purified by column chromatography onsilica gel, eluting with 20:1 chloroform:methanol to afford 219 mg ofthe title compound. MS (DCI/NH₃) m/e: 225/227 (M+H)⁺. ¹ H NMR (CDCl₃,300 MHz) δ: 8.07 (s, 1H), 7.25-7.18 (m, 2H), 4.02 (dd, J=9.1, 5.4 Hz,1H), 3.93 (dd, J=9.1, 5.4 Hz, 1H), 3.17-3.11 (m, 1H), 2.71-2.67 (m, 1H),2.49 (s, 3H), 2.38-2.29 (m, 1H), 2.10-1.98 (m, 1H), 1.91-1.68 (m, 3H).α!²⁵ _(D) =+64.5° (c=1.1, CHCl₃).

51b. 3-((1-methyl-2-(S)-pyrrolidinyl)methoxy-6-chloropyridinehydrochloride

The compound from step 51a was treated with HCl in ether according toExample 14c to afford the title compound. mp 120-122° C. MS (DCI/NH₃)m/e: 225/227 (M+H)⁺. ¹ H N1 R (D₂ O, 300 MHz) &: 8.13 (d, J=8.8 Hz, 1H),7.54 (dd, J=8.8, 3.0 Hz, 1H), 7.47 (d, J=8.8 Hz, 1H), 4.52 (dd, J=11.4,3.2 Hz, 1H), 4.35 (dd, J=11.4, 5.9 Hz, 1H), 3.98-3.90 (m, 1H), 3.78-3.70(m, 1H), 3.33-32.4 (m, 1H), 3.03 (s, 3H), 2.42-2.37 (m, 1H), 2.25-2.07(m, 3H). Anal. Calc. for C₁₁ H₁₆ N₂ OCl₂ : C, 50.20; H, 6.13; N, 10.64;Found C, 50.01; H, 6.19; N, 10.55.

EXAMPLE 52 3-(2-(S)-azetidinylmethoxy)-6-chloropyridine dihydrochloride

52a 3-((1-t-Butyloxycarbonyl-2-(S)-azetidinyl)methoxy)-6-chloropyridine

A 950 mg (5.1 mmol) sample of1-t-butyloxycarbonyl-2-(S)-azetidinemethanol, prepared as in Example 7babove, and 550 mg (4.25 mmol) of 2-chloro-5-hydroxypyridine were reactedwith triphenylphosphine and DEAD (5.1 mmol each) in 20 mL of THFaccording to the procedure of Example 14a, to give 1.09 g of the titlecompound. MS (DCI/NH₃) m/e: 299/301 (M+H)⁺. ¹ H NMR (DMSO-d₆, 300 MHz)δ: 8.14 (d, J=3.3 Hz, 1H), 7.48 (dd, J=8.8, 3.3 Hz, 1H), 7.37 (d, J=8.8Hz, 1H), 4.47-4.42 (m, 1H), 4.36 (dd, J=11.0, 4.4 Hz, 1H), 4.20 (dd,J=11.0, 3.3 Hz, 1H), 3.77 (t, J=7.7 Hz, 2H), 2.36-2.29 (m, 1H),2.19-2.12 (m, 1H), 1.36 (s, 9H). α!_(D) ²⁵ =-67.3° (c=1.1, CHCl₃).

52b. 3-(2-(S)-azetidinylmethoxy)-6-chloropyridine dihydrochloride

A 1.02 g sample of the compound from step 52a was stirred & with 10 mLof 4.5N HCl at room temperature for 30 minutes. The solvent was removed,and the residue was recrystallized from methanol/ether, to yield afterdrying 340 mg of the title compound. mp 113-11520 C. MS (DCI/NH₃) m/e:299/301 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ: 8.15 (d, J=3.0 Hz, 1H), 7.57(dd, J=8.9, 3.0 Hz, 1H), 7.47 (d, J=8.9 Hz, 1H), 4.98-4.89 (m, 1H), 4.42(d, J=4.4 Hz, 2H), 4.19-4.02 (m, 2H), 2.68 (q, J=8.5 Hz, 2H). Anal.Calc. for C₉ H₁₃ N₂ OCl₃ : C, 39.80; H, 4.82; N, 10.32; Found C, 40.12;H, 4.84; N, 10.35.

EXAMPLE 53 2-methyl-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridinedihydrochloride

To a 658 mg (2.25 mmol) sample of2-methyl-3-((1-t-butoxycarbonyl-2-(S)-pyrrolidinyl)methoxy)pyridine,from Example 17a above, was added 3 mL of a solution of formic acid andformaldehyde (1:2), and the reaction mixture was stirred at 80° C. for 3hours. The reaction was quenched with water and sat. K₂ CO₃, and themixture was extracted with-methylene chloride. The extract was driedover MgSO₄, reduced in volume, and the residue was purified bychromatography on silica gel, eluting with 5% to 10% methanol inchloroform. Removal of the solvent, and conversion of the residue intothe salt with HCl in ehter gave the title compound. mp 202-205° C. MS(DCI/NH₃) m/e: 193 (M+H)⁺. ¹ H NMR (D₂ O,300 ME) δ: 2.08-2.27.(m, 3H),2.43-2.48 (m, 1H), 2.55 (s, 3H), 3.09 (s, 3H), 3.31 (br s, 1H), 3.76 (brs, 1H), 4.04 (br s, 1H), 4.36 (dd, 1H, J=7, 11 Hz), 4.58 (dd, 1H, J=3.11 Hz), 7.50 (dd, 1H, J=5, 8.5 Hz), 7.65 (dd, 1H, J=1, 5 Hz), 8.12 (d,1H, J=1, 5 Hz). Anal. Calc. for C₁₂ H₁₈ N₂ O2.00•HCl: C, 51.62; H, 7.22;N, 10.03; Found C, 51.47; H, 735; N, 9.80. α!_(D) ²⁵ =+6.38⁰ (c=0.02,MeOH).

EXAMPLE 543-((1-methyl-2-(R)-pyrrolidinyl)methoxy)-5-trifluoromethylpyridinehydrochloride

54a. 3-((1-methyl-2-(R)-pyrrolidinyl)methoxy)-5-trifluoromethylpyridine

(R)-1-methyl-2-pyrrolidinemethanol (Aldrich Chemical Co.) was dissolvedin 8 mL of DMF and stirred under N₂, then 240 mg of NaH (80% dispersionin mineral oil) was added. The reaction mixture was stirred fifteenminutes, and 363 mg of 3-chloro-5-trifluoromethylpyridine (2.0 mmol) wasadded. The reaction mixture was stirred at 50° C. for 16 hours. Thevolatiles were removed under vacuum, and the residue was purified bychromatography on silica gel, eluting with 2:1 ethyl acetate:hexane togive 336 mg of the title product. MS (DCI/NH₃) m/e: 261 (M+H)⁺. ¹ H NMR(CDCl₃, 300 MHz) δ: 8.50 (d, J=0.6 Hz, 1H), 8.49 (d, J=3.0 Hz, 1H), 7.41(dd, J=0.6, 3.0 Hz, 1H), 4.12-3.96 (m, 2H), 3.21-3.10 (m, 1H), 2.80-2.65(m, 1H), 2.51 (s, 3H), 2.44-2.30 (m, 1H), 2.13-1.73 (m, 4H).

54b. 3-((1-methyl-2-(R)-pyrrolidinyl)methoxy)-5-trifluoromethylpyridinehydrochloride

The compound from step 54b was treated with HCl in ether according toExample 14c to afford 282 mg of the title compound. mp 246-248° C. MS(DCI/NH₃) m/e: 261 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ: 8.58 (d, J=0.6 Hz,1H), 8.56 (d, J=3.0 Hz, 1H), 7.83 (dd, J=0.6, 3.0 Hz, 1H), 4.60 (dd,J=11.0, 2.9 Hz, 1H), 4.33 (dd, J=10.6, 6.2 Hz, 1H), 4.05-3.93 (m, 1H),3.82-3.72 (m, 1H), 3.37-3.22 (m, 1H), 3.06 (s, 3H), 2.49-2.05 (m, 4H).Anal. Calc. for C₁₂ H₁₆ N₂ OF₃ Cl: C, 47.99; H, 5.50; N, 9.29; Found C,48.07; H, 5.40; N, 9.29. α!_(D) ²⁵ =+5.0° (c=1.00, methanol).

EXAMPLE 55

6chloro-3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine dihydrochloride

55a 6-chloro-3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine

A 625 mg sample of3-((1-t-butoxycarbonyl-2-(S)-pyrrolidinyl)methoxy)-6-chloropyridine,prepared as in Example 45a, was treated with 2 mL of 37%paraformaldehyde and 1 mL of formic acid at reflux for 16 hours. Thevolatiles were removed by evaporation, and the residue was dissolved in1 mL of 20% NaOH. The solution was extracted with CH₂ Cl₂ (3X), then theorganic layer was dried (Na₂ SO₄) and concentrated. The crude productwas purified by chromatography over silica gel, eluting with 100:1chloroform:methanol to afford 439 mg of the title compound. MS (DCI/NH₃)m/e: 227/229 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ: 8.09 (dd, J=2.1, 2.1Hz, 1H), 7.24-7.21 (m, 2H), 4.02 (dd, J=11.0, 3.0 Hz, 1H), 3.93 (dd,J=11.0, 5.8 Hz, 1H), 3.21-3.10 (m, 1H), 2.76-2.64 (m, 1H), 2.51 (s, 3H),2.40-2.28 (m, 1H), 2.12-1.98 (m, 1H), 1.97-1.68 (m, 4H).

55b. 6-chloro-3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridinedihydrochloride

The compound from step 55b was treated with HCl in ether according toExample 14c to afford 312 mg of the title compound. mp 96-98° C. MS(DCI/NH₃) m/e: 227/229 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ: 8.10 (d, J+3.0Hz, 1H), 7.54 (dd, J=8.8, 3.0 Hz, 1H), 7.45 (d, J=8.8 Hz, 1H), 4.50 (dd,t J=11.0, 3.0 Hz, 1H), 4.33 (dd, J=11.0, 5.8 Hz, 1H), 3.96-3.87 (m, 1H),3.80-3.69 (m, 1H), 3.30-3.18 (m, 1H), 3.03 (s, 3H), 2.45-2.00 (m, 4H).Anal. Calc. for C₁₁ H₁₅ N₂ OCl₂ •0.5 H₂ O: C, 48.49; H, 6.16; N, 10.29;Found C, 48.54; H, 6.30; N, 10. α!²⁵ _(D=-) 3.9° (c=1.05, MeOH).

EXAMPLE 56 5-bromo-3-((1-methyl-2-(R)-pyrrolidinyl)methoxypyridinehydrochloride

56a. 5-bromo-3-((1-methyl-2-(R)-pyrrolidinyl)methoxy)pyridine

(R)-1-methyl-2-pyrrolidinemethanol (430 mg, 13.74 mmol, Aldrich ChemicalCo.) was dissolved in 14 mL of DMF and stirred under N₂, then 123.4 mgof NaH (80% dispersion in mineral oil) was added. The reaction mixturewas stirred fifteen minutes, and 897.4 mg of 3,5-dibromomethylpyridinewas added. The reaction mixture was stirred at 50° C. for 16 hours. Thevolatiles were removed under vacuum, and the residue was purified bychromatography on silica gel to give 484 mg of the title product. MS(DCI/NH₃) m/e: 271/273 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ: 8.37 (d,J=1.8, Hz, 1H), 8.26 (d, J=2.7 Hz, 1H), 7.39 (dd, J=1.8, 2.7 Hz, 11H),4.01 (dd, J=3.3, 11.0 Hz, 1H), 3.93 (dd, J=6.9, 11.1, Hz, 1H), 3.20-3.10(m, 11H), 3.93 (dd, J=6.9, 11.1 Hz, 1H), 3.20-3.10 (m, 1H), 2.76-2.64(m, 1H), 2.49 (s, 3H), 2.40-2.28 (m, 1H), 2.44-2.00 (m, 4H).

56b. 5-bromo-3-((1-methyl-2-(R)-pyrrolidinyl)methoxy)pyridinehydrochloride

The compound from step 55b was treated with HCl in ether according toExample 14c to afford 362 mg of the title compound. mp 205° C. (dec). MS(DCI/NH₃) m/e: 271/273 (M+H)⁺, ¹ H NMR (D₂ O, 300 MHz) δ: 8.45 (d, J=1.5Hz, 1H), 8.38 (d, J=2.7 Hz, 1H-), 8.01 (dd, J=1.5, 2.7 Hz, 1H), 4.56(dd, J=3.0, 11.4 HZ, 1H), 4.40 (dd, J=6.3, 11.4 Hz, 1H), 3.98-3.86 (m,1H), 3.80-3.72 (m, 1H), 3.30-3.20 (m, 1H), 3.03 (s, 3H), 2.44-2.00 (m,4H). Anal. Calc. for C₁₂ H₁₆ N₂ OBrCl•0.18 HCl: C, 39.23; H, 5.03; N,8.32; Found C, 39.11; H, 4.90; N, 8.32. α!²⁵ _(D) ==3.9° (c=1.05,methanol).

EXAMPLE 57 3-((1-allyl-2-(S)-pyrrolidinyl)methoxy)-5-bromopyridinedihydrochloride

57a 1-allyl-2-(S)-pyrrolidinemethanol

(S)-1-methyl-2-pyrrolidinemethanol (5.10 g, 50 mmol, Aldrich ChemicalCo.) was dissolved in 50 mL of CHCl₃, then 5.25 mL of allyl bromide and8.34 mL of triethylamine were added. The reaction mixture was stirred atroom temperature for 2 hours, then the volatiles were removed underreduced pressure. The residue was purified by chromatography on silicagel to give 6.3 g of the title product. MS (DCI/NH₃) m/e: 142 (M+H)⁺. ¹H NMR (CDCI₃, 300 MHz) δ: 6.05-5.90 (m, 1H), 5.33-5.17 (m, 2H),3.77-3.68 (m, 1H), 3.58-3.47 (m, 2H), 3.32-3.20 (m, 1H), 3.16-3.05 (m,1H), 2.90-2.78 (m, 1H), 2.53-2.40 (m, 1H), 2.02-1.73 (m, 4H).

57b. 3-((1-allyl-2-(S)-pyrrolidinyl)methoxy)-5-bromopyridine

A 230 mg sample of 1-allyl-2-(S)-pyrrolidinemethanol, from step 57aabove, was dissolved in 8 mL of DMF and stirred under N₂, then 104 mg ofNaH (80% dispersion in mineral oil) was added The reaction mixture wasstirred fifteen minutes, and 489.8 mg of 3,5dibromomethylpyridine wasadded. The reaction mixture was stirred at 60° C. for 4 hours. Thevolatiles were removed under vacuum, and the residue was purified bychromatography on silica gel to give 230 mg of the title product. MS(DCI/NH₃) m/e: 297/299 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ: 8.28 (d,J=1.8 Hz, 1H), 8.24 (d, J+2.6 Hz, 1H), 7.48 (dd, J=1.8, 2.6 Hz, 1H),6.02-5.88 (m, 1H), 5.30-5.12 (m, 2H), 4.15-3.90 (m, 1H), 3.96-3.82 (m,1H), 3.60-3.43 (m, 1H), 3.23-3.05 (m, 2H), 3.03-2.90 (m, 1H), 2.45-2.32(m, 1H), 2.10-1.95 (m, 1H), 1.90-1.70 (m, 3H).

57c. 3-((1-allyl-2-(S)-pyrrolidinyl)methoxy)-5-bromopyridinedihydrochloride

The compound from step 57b was treated with HCl in ether according toExample 14c to afford 198 mg of the title compound. mp 183-185° C. MS(DCI/NH₃) m/e: 297/299 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ: 8.43 (d, J=1.8Hz, 1H), 8.36 (d, J=2.6 Hz), 7.94 (dd, J=1i8, 2.6 Hz, 1H), 6.04-5.92 (m,1H), 5.64-5.57 (m, 2H), 4.58-4.48 (m, 1H), 4.42-4.36 (m, 1H), 4.12-4.02(m, 2H), 3.94-3.88 (m, 1H), 3.76-3.64 (m, 1H), 3.36-3.25 (m, 1H),2.43-2.31 (m, 1H), 2.22-2.00 (m, 3H). Anal. Calc. for C₁₃ H₁₉ N₂ OBrCl₂: C, 42.19; H, 5.17; N, 7.57; Found C, 42.32; H, 5.10; N, 7.79. α!²⁵_(D) =-14.7° (c=1.01, methanol).

EXAMPLE 58 3-(2-(R)-pyrrolidinylmethoxy)-6-chloropyridine hydrochloride

Following the procedures described in Example 45 steps a-c, substituting(R)-1-t-butoxycarbonyl-2-pyrrolidinemethanol for the(S)-1-t-butoxycarbonyl-2-pyrrolidinemethanol of step 45a thereof, thetitle compound was prepared. mp 157-159° C. MS (DCI/NH₃) m/e: 213/215(M+H)⁺ and 230/232 (M+NH₄)⁺. ¹ H NMR (D₂ O, 300 MHz) δ: 8.10 (d, J=3.0Hz, 1H), 7.53-7.43 (m, 2H), 4.45 (dd, J=10.7, 7.7 Hz, 1H), 4.15-4.08 (m,1H), 3.41 (t, J=7.2 Hz, 2H), 2.34-1.88 (m, 4H). Anal. Calc. for C₁₀ H₁₄Cl₂ N₂ O•0.3 HCl: C, 46.18; H, 5.54; N, 10.77; Found C, 46.35; H, 5.51;N, 10.66.

EXAMPLE 59 3-((1-methyl-2-(S)-azetidinyl)methoxy)-6-methylpyridinedihydrochloride

59a. 3-((1-BOC-2-(S)-azetidinyl)methoxy)-6-methylpyridine

A 3.74 g (20 mmol) sample of1-t-butyloxycarbonyl-2-(S)-azetidinemethanol, prepared as in Example 7babove, and 3.27 g (30 mmol) of 2-methyl-5hydroxypyridine were reactedwith triphenylphosphine and DEAD (30 mmol each) in 100 mL of THFaccording to the procedure of Example 14a, to give the title compound.

59b. 3-((1-methyl-2-(S)-azetidinyl)methoxy)-6-methylpyridinedihydrochloride

A 1.3 g sample of the compound from step 59a above was dissolved in 6 mLof methylene chloride, the solution was cooled to 0° C., and 4 mL of TFAwas added. The reaction mixture was stirred at 0° C. for 3 hours, thenpoured into a satd solution of K₂ CO₃. The organic layer was separated,the aqueous layer extracted with additional methylene chloride, theorganics combined, and the solvent removed. The residue was dissolved inethanol, the solution was cooled to 0° C., and excess NaCNBH₃ was added.Two mL of HCHO were added, the pH was adjusted with acetic acid, usingbromocresol as an indicator, and the reaction mixture was stirred for 16hours. The reaction was quenched by pouring it into satd K₂ CO₃solution. The mixture was extracted with methylene chloride, the extractwas dried over MgSO₄, and the solvent was removed. The residual oil waspurified by chromatography on silica gel, eluting with 100: 1 to 95:5CHCl₃ :methanol containing 0.5% NH₄ OH. This compound was treated withHCl in ether according to Example 14c to afford 362 mg of the titlecompound. MS (DCI/NH₃) m/e: 193 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ: 8.33(d, J=2.2 Hz, 1H), 7.92 (dd, J=2.6, 8.8 Hz, 1H), 7.66 (d, J=8.8 Hz, 1H),7.66 (d, J=8.8 Hz, 1H), 4.87-4.77 (m, 1H), 4.57-4.44 (m, 2H), 4.33-4.23(m, 1H), 4.01 (q, J=9.6 Hz, 1H), 3.00 (s, 3H), 2.73-2.61 (m, 2H), 2.64(s, 3H). Anal. Calc. for C₁₁ H₁₆ N₂ O•2 HCl•0.4 H₂ O: C, 49.88; H, 6.84;N, 10.56; Found C, 48.25; H, 6.96; N, 10.28.

EXAMPLE 60 3-((cis-1-methyl-3-propyl-2-pyrrolidinyl)methoxy)pyridinedihydrochloride

60a. cis-1-BOC-3-propyl-2-pyrrolidinemethanol

A 400 mg (1.6 mmol) sample of 1-BOC-3-propyl-2-carboxylic acid methylester (prepared according to Chung et al., J. Org. Chem., 55:270-275(1990)) was dissolved in 12 mL of THF and cooled to 0° C. To thissolution was added 3.0 mL of 1M LAH, and the reaction was stirred at 0°C. for 30 minutes. The reaction was quenched by sequential addition of0.11 mL of H₂ O, 0.11 mL of 40% NaOH and 3.00 mL of H₂ O, and themixture was stirred for 30 minutes. The mixture was filtered, and thefiltrate was concentrated. The residue was purified by chromatography onsilica gel to give 240 mg of the title compound.

60b. 3-((cis-1-BOC-3-propyl-2-pyrrolidinyl)methoxypyridine

A 220 mg (0.96 mmol) sample of cis-1-BOC-3-propyl-2-pyrrolidinemethanol,prepared as in Example 60a above, and 137 g (1.44 mmol) of3-hydroxypyridine were reacted with triphenylphosphine and DEAD (1.44mmol each) in 10 mL of THF according to the procedure of Example 14a, togive 190 mg of the title compound. MS (DCI/NH₃) m/e: 321 (M+H)⁺. ¹ H NMR(CDCl₃, 300 MHz) δ: 8.29 (s, 1H), 8.19 (m, 1H), 7.27 (m, 1H), 7.21 (m,1H), 4.33 (q, 1H), 4.18-3.80 (m, 2H), 3.52-3.2 (m, 2H), 2.32-2.20 (m,1H), 2.05-1.94 (m, 1H), 1.80-1.73 (m, 1H), 1.58-1.23 (m, 4H), 1.48 (s,9H), 0.92 (m, 3H).

60c. 37-((cis-1-methyl-3-propyl-2-pyrrolidinylmethoxy)pyridine

A 100 mg (0.31 mmol) sample of3-(cis-1-BOC-3-propyl-2-pyrrolidinylmethoxy)pyridine, from step 60babove, was treated with 1.9 mL of formic acid and 3.83 mL of 37% HCHO at67° C. for 16 hr. The reaction was quenched by pouring it into satd K₂CO₃ solution. The mixture was extracted with methylene chloride, theextract was dried over MgSO₄, and the solvent was removed to give 70 mgof the title compound. MS (DCI/NH₃) m/e: 235 (M+H)⁺. ¹ H NMR (CDCl₃, 300MHz) δ: 8.34 (m, 1H), 8.22 (m, 11H), 7.21 (m, 2H), 4.50 (m, 1H), 3.95(m, 1H), 3.12 (m, 1H), 2.82-2.72 (m, 1H), 2.52 (s, 3H), 2.38-2.22 (m,2H), 2.02-1.91 (m, 1H), 1.60-1.35 (m, 4H), 1.30-1.23 (m, 3H), 0.82 (t,3H).

60d. 3-((cis-1-methyl-3-propyl-2-pyrrolidinyl)methoxy)pyridinedihydrochloride

The compound from step 60c was treated with HCl in ether according toExample 14c to afford the title compound. MS (DCI/NH₃) m/e: 235 (M+H)⁺.¹ H NMR (D₂ O, 300 MHz) δ: 8.51 (d, J=2.9 Hz, 1H), 8.42 (d, J=5.5 Hz,1H), 4.63 (m, 1H), 4.50 (m, 1H), 2.04 (m, 1H), 3.83 (m, 1H), 3.18 (m,1H), 3.07 (s, 3H), 2.78 (m, 1H), 2.42-2.30 (m, 1H), 1.58-1.28 (m, 4H),6.9 (t, J=7.0, 3H). Anal. Calc. for C₁₄ H₂₂ N₂ O•2 HCl•1 H₂ O: C, 51.69;H, 8.06; N, 8.61; Found C, 51.67; H, 7.79; N, 8.19. α!²⁵ _(D) =+16.5°(c=1.01, methanol).

EXAMPLE 61 3-((cis-3-propyl-2-pyrrolidinyl)methoxy)pyridinedihydrochloride

61a. 3-((cis-3-propyl-2-pyrrolidinyl)methoxy pyridine

A 160 mg (0.5 mmol) sample of3-(cis-1-BOC-3-propyl-2-pyrrolidinylmethoxy)pyridine, from step 60babove, was dissolved in 2 mL of methylene chloride and stirred with 1 mLof TFA for 16 hours at room temperature. The solvent was removed undervacuum, and the residue was adjusted to pH 8 with NaHCO₃. The mixturewas extracted with methylene chloride, and the extract was dried overMgSO₄ The residue was purified by chromatography on silica gel, elutingwith 10:2:0.2 CHCl₃ :methanol:ammonium hydroxide, to give 60 mg of thetitle product MS (DCI/NH₃) m/e: 221 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ:8.33 (m, 1H), 8.24 (m, 1H), 7.22 (m, 2H), 4.10 (m, 1H), 4.00 (m, 1H),3.69 (m, 1H), 3.24 (m, 1H), 3.07 (m, 1H), 2.33 (m, 1H), 2.07 (m, 1H),1.65 (m, 1H), 1.39 (m, 4H), 0.92 (m, 3H).

61a. 3-((cis-3-propyl-2-pyrrolidinyl)methoxy)pyridine dihydrochloride

A 120 mg sample of the compound from step 61a was treated with HCl inether according to Example 14c to afford 120 mg of the title compound.mp 183-185° C. MS (DCI/NH₃) m/e: 221 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ:834 (s, 1H), 8.25 (d, J=4.04, 1H), 7.61 (m, 1H), 7.52 (m, 1H), 4.45 (dd,J=3.7, 10.7 Hz, 1H), 4.27 (m, 1H), 4.16 (m, 1H), 3.54 (m, 1H), 3.35 (m,1H), 2.55 (m, 1H), 2.30 (m, 1H), 1.92 (m, 1H), 1.57-1.3 (m, 4H), 0.92(t, J=6.9 Hz, 3H). Anal. Calc. for C₁₃ H₂₀ N₂ O•1.6 HCl•0.3 H₂ 0: C,54.97; H, 7.88; N, 9.85; Found C, 55.37; H, 7.48; N, 9.43.

EXAMPLE 62 3-(2-(R)-azetidinylmethoxylpyridine dihydrochloride

62a. 1-BOC-azetidine-2-(R)-carboxylic acid

A 4.98 g (19.50 mmol) sample of the1-(p-toluenesulfonyl)azetidine-2-(R)-carboxylic acid (prepared accordingto the procedure of Miyoshi et al., Chem. Lett., 1973:5) was suspendedin 100 mL of liq. NH₃ at -78° C., and sodium metal was added over aperiod of 1 hour until a blue color persisted. The reaction mixture wasstirred for 16 hours, slowly allowing the reaction mixture to rise toroom temperature. Excess K₂ CO₃ was added (3.23 g), followed by 250 mLof THF and 10 mL of isopropanol. To this solution was added 25 mL of H₂O and 5.38 mL (23.9 mmol) of di-t-butyl dicarbonate, and the reactionmixture was stirred for 18 hours. The reaction was quenched by additionof 100 mL of 10% NaOH, and the mixture was extracted with ether. Theaqueous layer was acidified to pH 1 with 10% HCl, and this solution wasextracted with methylene chloride. The methylene chloride extract wasdried over MgSO₄ and concentrated to afford 1.92 g of the title compoundas an oil.

62b. 1-BOC-2-(R)-azetidinemethanol

To an ice-cooled solution of the product of Example 62a (1.9 g, 9.44mmol) in tetrahydrofuran (100 ml) was added borane/THF complex (1M, 42.5mL, 42.5 mmol) under nitrogen. The reaction was gradually warmed to roomtemperature and stirred for 18 hours, then quenched by addition of 75 mLof 10% NH₄ Cl. The mixture was extracted with methylene chloride, whichwas washed with 10%o HCl and brine, dried over and concentrated toafford 1.18 g of the title product as an oil.

62c. 1-BOC-2-(R)-azetidinylmethoxy pyridine

A 1.10 g (5.87 mmol) sample of 1-BOC-2-(R)-azetidinemethanol, preparedin step 62b above, and 588 g (5.87 mmol) of 3-hydroxypyridine werereacted with triphenylphosphine and DEAD (7.05 mmol each) in 100 mL ofTHF according to the procedure of Example 14a, to give the titlecompound.

62d. 2-(R)-azetidinylmethoxy)pyridine

The compound from step 62c above (147 mg) was treated with 5 mL ofhydrogen chloride saturated ethanol for 4 hours. The solvents wereremoved under vacuum to give the title compound. MS (DCI/NH₃) m/e 165(M+H)⁺, 182 (M+NH₄)⁺. ¹ NMR (DMSO, 300 MHz) δ: 2.36-2.64 (m, 2H),3.84-4.02 (m, 2H), 4.37-4.53 (m, 2H), 4.69-4.81 (m, 1H), 7.54-7.62 (m,1H), 7.65-7.73 (m, 1H), 8.34 (dd, 1H, 8.49 (d, 1H), 9.14 (m, 2H). Anal.calc. for C₉ H₁₂ N₂ O•2.0 HCl•0.2 CH₂ OH: C, 45.83; H, 6.22; N, 11.37.Found: C, 45.86; H, 6.12; N, 11.17.

Example 63 3-((l-methyl-2-(R)-azetidinyl)methoxy)pyridinedihydrochloride

A 142 mg (0.537 mmol) sample of 1-BOC-2-(R)-azetidinylmethoxy)-pyridine,from Example 62c above, was treated with 5 mL of formic acid and 5 mL of37% HCHO at reflux for 14 hr. The reaction was quenched by addition ofH₂ O The mixture was adjusted to pH 7 with NaHCO₃ and extracted withmethylene chloride, the extract was dried over MgSO₄, and the solventwas removed to give the title compound, which was converted to the saltas in Example 62d above. MS (DCI/NH₃) m/e 179 (M+H)⁺, 196 (M+NH₄)⁺. ¹NMR (DMSO, 300 MHz) δ: 2.33-2.48 (m, 2H), 2.87, 2.88 (two s, 3H),3.79-3.96 (m, 1H), 3.99-4.13 (m, 1H), 4.44-4.67 (m, 2H), 4.67-4.81 (m,1H), 7.67-7.73 (m, 1H), 7.81-7.89 (m, 1H), 8.41 (dd, 1H), 8.58 (d, 1H),10.71 (br m, 1H). Anal. calc. for C₉ H₁₂ N₂ O•2.0 HCl•0.6 H₂ O•0.2 CH₂OH: C, 46.87; H, 6.99; N, 10.12. Found: C, 46.77; H, 7.01; N, 9.93.

EXAMPLE 64 4methyl-3-(2-(S)-azetidinylmethoxy)pyridine dihydrochloride

A 0.82 g (4.4 mmol) sample of 1-BOC-2-(S)-azetidinemethanol, prepared asin Example 7b above, and 0.48 g (4.4 mmol) of 4methyl-3-hydroxypyridine,prepared as in Example 27b above, were reacted with triphenylphosphineand DEAD (5.28 mmol each) in 15 mL of THF according to the procedure ofExample 14a. The BOC group was removed as in Example 14 b to give thefree base of the title compound. The base was converted to the salt asin Example 62d above. mp 149-152° C. MS (DCI/NH₃) m/e 179 (M+H)⁺, 196(M+NH₄)⁺. ¹ NMR (D₂ O, 300 MHz) δ: 8.28 (br s, 1H), 8.24 (m, 1H), 7.59(d, J=5.2 Hz, 1H), 4.98 (m, 1H), 4.53 (m, 2H), 4.16 (m, 2H1), 2.75 (d,J=8.4 Hz, 2H), 2.46 (s, 3H). Anal. calc. for C₁₀ H₁₆ Cl₂ N₂ O•0.3 HCl:C, 45.83; H, 6.27; N, 10.69. Found: C, 45.90; H, 6.45; N, 10.34.

EXAMPLE 65 5-bromo-3-(2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

65 5-bromo-3-methoxypyridine

To a suspension of 12 g of 3,5-dibromopyridine and 40 g of 60% NaH inDMF was added 4.05 mL of methanol, and the reaction mixture was stirredfor 4 hours at room temperature and 1 hour at 60° C. The DMF was removedunder reduced pressure, and the residue was taken directly to the nextstep. MS (DCI/NH₃) m/e 188/190 (M+H)⁺, 205/207 (M+NH₄)⁺. ¹ H NMR (CDCl₃,300 MHz) δ: 8.32 (d, J=1.8 Hz, 1H), 8.27 (d, J=2.6 Hz, 1H), 7.42 (dd,J=1.8, 2.6 Hz, 1H), 3.88 (s, 3H).

65b. 5-bromo-3-hydroxypyridine

The compound from the previous step was heated at relux with 60 mL ofHBr for 16 hours. The reaction was quenched with excess NaHCO3, and thebasic mixture was extracted with ethyl acetate, and the extract wasdried over Na2SO4. The solvent was removed, and the residue waschromatographed on silica gel, eluting with 10% methanol in chloroform.MS (DCI/NH₃) m/e 174/176 (M+H)⁺, 191/193 (M+NH₄)⁺. ¹ H NMR (CDCl₃, 300MHz) δ: 8.27 (d, J=1.8 Hz, 1H), 8.23 (d, J=2.6 Hz, 1H), 7.44 (dd, J=1.8,2.6 Hz).

65c. 5-bromo-3-(1-BOC-2-(S)-pyrrolidinylmethoxy)pyridine

A 332 mg (1.2 mmol) sample of 1-BOC-2-(S)-azetidinemethanol, prepared asin Example 7b above, and 240 mg (1.38 mmol) of5-bromo-3-hydroxypyridine, prepared as in Example 65b above, werereacted with triphenylphosphine and DEAD (1.2 mmol each) in 5 mL of THFaccording to the procedure of Example 14a, to give 355 mg of the titlecompound. MS (DCI/NH₃) m/e 357/359 (M+H)⁺, 374/376 (M+NH₄)⁺. ¹ H NMR(CDCl₃, 300 MHz) δ: 8.28 (d, J=1.8 Hz, 1H), 8.24 (d, J=2.6 Hz, 1H), 7.44(dd, J-1.8, 2.6 Hz, 1H), 8.24 (d, J=2.6 Hz, 1H), 7.44 (dd, J=1.8, 2.6Hz, 1H), 4.21-4.05 (m, 2H), 4.03-3.92 (m, 1H), 3.48-3.82 (m, 2H),2.10-1.80 (m, 4H), 1.47 (s, 9H).

65d 5-bromo-3-(2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

The BOC group was removed from the compound of 65c as in Example 14b togive the free base of the title compound The base was converted to thesalt as in Example 62d above. mp 168-170° C. MS (DCI/NH₃) m/e 257/259(M+H)⁺, 274/276 (M+NH₄)⁺. ¹ H NMR (D₂ O, 300 MHz) δ: 8.39 (d, J=1.8 Hz,1H), 8.32 (d, J=2.6 Hz, 1H), 7.90 (dd, J=1.8, 2.6 Hz, 1H), 4.50 (dd,J=11, 3.6 Hz, 1H), 4.28 (dd, J=11, 7.7 Hz, 1H), 4.16-4.08 (m, 1H), 3.41(t, J=7.2 Hz, 2H). Anal. Calc. for C₁₀ H₁₄ N₂ OBrCl•0.9 HCl: C, 36.80;H, 4.60; N, 8.58; Found C, 36.93; H, 4.52; N, 8.58. α!²⁵ _(D) =+8.65°(c=1.04, methanol).

EXAMPLE 66 3-(2-(S)-pyrrolidinylmethoxy)-5-trifluoromethylpyridinedihydrochloride

66a. 3-benzyloxy-5-trifluoromethylpyridine

To a 3.63 g (20 mmol) sample of 3-chloro-5-trifluoromethylpyridinedissolved in 15 mL of DMF and cooled to 0° C. was added 960 mg of NaH(60%), 2.07 mL of benzyl alcohol was added slowly. The reaction mixturewas stirred for 2 hours at 40° C. The solvent was then evaporated invacuo and the mixture diluted with chloroform, washed with saturatedNaHCO₃ and a brine solution. The organic layer was then dried overMgSO₄. The resulting crude material was purified by flash chromatographyon silica gel to give the title product MS (DCI/NH₃) m/e 154(M+H)⁺. ¹HNMR (CDCl₃, 300 MHz) δ: 8.56 (d, J=1.8 Hz, 1H), 8.47 (d, J=0.9 Hz, 1H),7.51 (dd, J=1, 0.9 Hz, 1H).

66b. 3-hydroxy-5-trifluoromethylpyridine

The product from step a above (1.95 g) was dissolved in 10 mL ofmethanol and hydrogenated over Pd/C (5%, 97.5 mg) at I atm H₂ for 16hours. The catalyst was removed, and the solvent was evaporated. Theresidue was purified by flash chromatography on silica gel to give thetitle compound. MS (DCCI/NH₃) m/e 163 (M+H)⁺, 181 (M+NH₄)⁺. ¹ H No(CDCI₃, 300 MHz) δ: 8.57 (d, J=1.8 Hz, 1H), 8.51 (d, J=0.9 Hz, 1H),7.48-7.25 (m, 6h), 5.17 (s, 2H).

66c. 3-((1-BOC-2-(S)-pyrrolidinyl)methoxy)-5trifluoromethylpyridine

A 333 mg (1.20 mmol) sample of 1-BOC-2-(S)-azetidinemethanol, preparedas in Example 7b above, and 230 mg (1.30 mmol) of3-hydroxy-5-trifluoromethylpyridine, from step 66b above, were reactedwith triphenylphosphine and DEAD (1.2 mmol each) in 5 mL of THFaccording to the procedure of Example 14a, to give 360 mg of the titlecompound. MS (D)CI/NH₃) m/e 347 (M+H)⁺. ¹ H so NMR (CDCl₃, 300 MHz) δ:8.50 (s, 1H), 8.48 (s, 1H), 7.46 (s, 1H), 4.28-3.90 (m, 3H), 3.48-3.84(m, 2H), 2.12-1.87 (m, 4H).

66d. 3-(2-(S)-pyrrolidinylmethoxy)-5trifluoromethylpyridinedihydrochloride

The BOC group was removed from the compound of 66c as in Example 14b togive the free base of the title compound. The base was converted to thesalt as in Example 62d above. mp 158-161° C. MS (DCI/NH₃) m/e 247(M+H)⁺, 264 (M+NH₄)⁺. ¹ H NMR (D₂ O, 300 MHz) δ: 8.60 (d, J=O.6 Hz, 1H),8.55 (d, J=3.0 Hz, 1H), 7.88 (dd, J=0.6, 3.0 Hz, 1H), 4.54 (dd, J=10.6,3.7 Hz, 1H), 4.32 (dd, J=10.6, 7.7 Hz, 1H), 4.20-4.11 (m, 1H), 3.42 (t,J=6.9 Hz, 2H), 2.35-1.90 (m, 4H). Anal. Calc. for C₁₁ H₁₄ N₂ OClF₃ : C,41.40; H, 4.74; N, 8.78; Found C, 41.38; H, 4.57; N, 8.77. α!²⁵ _(D)=+13.0° (c=0.50, methanol).

EXAMPLE 67 3-(2-(S)-azetidinylmethoxy)-5-bromopyridine dihydrochloride

67a 3-((1-BOC-2-(S)-azetidinyl)methoxy)-5-bromopyridine

A 619.3 mg (3.31 mmol) sample of-1-BOC-2-(S)-azetidinemethanol, preparedas in Example 7b above, and 480 mg (2.76 mmol) of5-bromo-3-hydroxypyridine, from Example 65b above, were reacted withtriphenylphosphine and DEAD (3.31 mmol each) in 10 mL of THF accordingto the procedure of Example 14a, to give 887 mg of the title compound.MS (DCI/NH₃) m/e 243/246 (M+H)⁺, 260/262 (M+NH₄)⁺. ¹ H NMR (CDCl₃, 300MHz) δ: 8.35-8.25 (br, 2H), 7.44 (s, 1H), 4.55-4.47 (m, 1H), 4.39-4.29(m, 1H), 4.16-4.10 (m, 1H), 3.98-3.85 (m, 2H), 2.42-2.33 (m, 2H), 1.42(s, 9H).

67b. 3-(2-(S)-azetidinylmethoxy)-5-bromopyridine dihydrochloride

The BOC group was removed from the compound of 67a by hydrolysis with 4MHCl in dioxane to give the free base of the title compound. The base wasconverted to the salt as in Example 62d above, followed byrecrystallization from methanol/ether. mp 163-165C. MS (DCI/NH₃) m/e243/246 (M+H)⁺, 260/262 (M+NH₄)⁺. ¹ H NMR (D₂ O, 300 MHz) δ: 8.36 (d,J=1.8 Hz, 1H), 8.32 (d, J=2.6 Hz, 1H), 7.84 (dd, J=1.8, 2.6 Hz, 1H),4.98-4.90 (m, 1H), 4.43 (d, J=4.0 Hz, 2H), 4.20-4.02 (m, 2H), 2.67 (q,J=8.5 Hz, 2H). Anal. calc. for C₉ H₁₃ N₂ OBrCl₂ : C, 34.21; H, 4.15; N,8.86. Found: C, 34.18; H, 4.17; N, 8.89. α!²⁵ _(d) =-5.1° (c=0.57,methanol).

EXAMPLE 68 3-((1-methyl-2-(S)-azetidinyl)methoxy-5-bromopyridinedihydrochloride

68a. 3-((1-methyl-2-(S)-azetidinyl)methoxy)-5-bromopyridine

A 480 mg sample of the free base of3-(2-(S)-azetidinylmethoxy)-5-bromopyridine, from Example 67 above, wasdissolved in 4 mL of acetic acid treated with 1 mL of 37% HCHO and 500mg of NaBH₃ CN at 0° C. for 4 hr. The solvents were removed underreduced pressure The residue was basified with NaHCO₃ solution. Themixture was extracted with methylene chloride, the extract was driedover MgSO₄, and the solvent was removed. The residue was purified bychromatography on silica gel, eluting with 200:1 and 100: 1chloroform:methanol to give 68 mg of the title compound. MS (DCI/NH₃)m/e: 257/259 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ: 8.28 (d, J=1.9 Hz, 1H),8.26 (d, J=2.6 Hz, 1H), 7.38 (dd, J=1.9, 2.6 Hz, 1H), 4.02 (d, J=6.3 Hz,2H), 3.51-3.44 (m, 1H), 3.43-3.37 (m, 1H), 2.93-2.84 (m, 1H), 2.41 (s,3H), 2.13-2.03 (m, 2H).

68b. 3-((1-methyl-2-(S)-azetidinyl)methoxy)-5-bromopyridinedihydrochloride

The compound from step 60c was treated with HCl in ether according toExample 14c to afford the title compound. mp 160-162° C. MS (DCI/NH₃)m/e: 257/259 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ: 8.34 (d, J=1.9 Hz, 1H),8.31 (d, J=2.6 Hz, 1H), 7.78 (dd, J=1.9, 2.6 Hz, 1H), 4.85-4.74 (m, 1H),4.49 (dd, J=11.8, 2.9 Hz), 4.40 (dd, J=11.0, 7.4 Hz, 1H), 4.27 (m, 1H),4.00 (q, J=10.3 Hz, 1H), 2.99 (s, 3H), 2.74-2.55 (m, 2H). Anal. Calc.for C₁₀ H₁₅ N₂ OBrCl₂ : C, 36.39; H, 4.58; N, 8.49; Found C, 36.48; H,4.56; N, 8.70. α!²⁵ _(D) =-16.8° (c=0.51, methanol).

EXAMPLE 69 3-(2-(R)-pyrrolidinylmethoxy)-5-trifluoromethylpyridinedihydrochloride

69a 3-(1-BOC-2-(R)-pyrrolidinylmethoxy)-5-trifluoromethylpyridine

A 332.9. mg (1.56 mmol) sample of(R)-1-t-butoxycarbonyl-2-pyrrolidinemethanol and 224.9 mg (1.30 mmol) of3-hydroxy-5-trifluoromethylpyridine were reacted with triphenylphosphineand DEAD (1.56 mmol each) in 5 mL of THF according to the procedure ofExample 14a, to give 386 mg of the title compound,-MS (DCI/NH₃) m/e 347(M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ: 8.50 (s, 1H), 8.48 (s, 1H), 7.46 (s,1H), 4.28-3.90 (m, 3H), 3.48-3.84 (m, 2H), 2.12-1.87 (m, 4H), 1.47 (s,9H).

69a. 3-(2-(R)-pyrrolidinylmethoxy)-5-trifluoromethylpyridinedihydrochloride

A 380 mg sample of the compound from step 69a above was dissolved in 5mL of dioxane and treated with 4M HCl in dioxane. The salt wascollected, washed and dried, to afford 129 mg of the title compound. mp169-171° C. MS (DCI/NH₃) m/e 347 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ: 8.60(d, J=0.6 Hz, 1H), 8.55 (d, J=3.0 Hz, 1H), 7.88 (dd, I=0.6, 3.0 Hz, 1H),4.54 (dd, J=10.6, 3.7 Hz, 1H), 4.32 (dd, J=10.6, 7.7 Hz, 1H), 4.20-4.11(m, 1H), 3.42 (t, J=6.9 Hz, 2H), 2.35-1.90 (m, 4H). Anal. Calc. for C₁₁H₁₄ N₂ OF₃ CI•0.7 HCl: C, 42.87; H, 4.81; N, 9.09; Found C, 42.96; H,4.55; N, 9.05. α!²⁵ D=-9.2° (c=0.52, MeOH).

EXAMPLE 70 3-(2-(S)-azetidinylmethoxy)-S-trifluoromethylpyridinedihydrochloride

70a. 3-((1-BOC-2-(S)-azetidinyl)methoxy)-5-trifluoromethylpyridine

A 771.9.3 mg (4.13 mmol) sample of 1-t-BOC-2-(S)-azetidinemethanol,prepared as in Example 7b above, and 560 mg (3.44 mmol) of3-hydroxy-5-trifluoromethylpyridine, from Example 66b above, werereacted with triphenylphosphine and DEAD (4.13 mmol each) in 15 mL ofTHF according to the procedure of Example 14a, to give 683 mg of thetitle compound. MS (DCI/NH₃) m/e 333 (M+M)⁺. ¹ H NMR (CDCl₃,300 MHz) δ:8.54 (d, 1.8 Hz, 1H), 8.51 (d, J=0.9 Hz, 1H), 7.93 (dd, J=0.9, 1.8 Hz,1H), 4.59-4.50 (m, 1H), 4.94-4.86 (m, 1H), 4.22-4.17 (m, 1H), 3.90 (t,J=7.3 Hz, 2H), 2.43-2.27 (m, 2H), 1.43 (s, 9H).

70b. 3-(2-(S)-azetidinylmethoxy-5-trifluoromethylpyridinedihydrochloride

A 680 mg sample of the compound from step 69a above was dissolved in 5mL of dioxane and treated with 1.13 mL of 4M HCl in HCl in dioxane at 0°C. for 1.5 hours. The salt was collected, washed and dried, to afford 60mg of the title compound. mp 154-156° C. MS (DCI/NH₃) m/e 233 (M+H)⁺,250 (M+NH₄)⁺. ¹ H NMR (D₂ O, 300 MHz) δ: 8.61 (d, 0.9 Hz, 1H), 8.60 (d,J=1.8 Hz, 1H), 7.93 (dd, J=0.9, 1.8 Hz, 1H), 5.04-4.95 (m, 1H), 4.51 (d,J=4.1 Hz, 2H), 4.22-4.04 (m, 2H), 2.70 (q, J=8.4 Hz, 2H). Anal. Calc.for C₁₀ H₁₁ N₂ OF₃ •1.8 HCl: C, 40.33; H, 4.33; N, 9.41; Found C, 40.09;H, 4.37; N, 9.35. α!²⁵ _(D) =-3.3° (c=0.52, MeOH).

EXAMPLE 71 5n-butyl-3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridinedihydrochloride

To a 1.08 g (4 mmol) sample of5-bromo-3-((1-methyl-2-(S)-pyrrolidinyl)-methoxy)pyridine, prepared asin Example 56a above, dissolved in 40 mL of dry ether and cooled to 0°C. was added 6.0 mL of n-butylmagnesium chloride and 13.0 mg ofNi(dppp)Cl, and the reaction mixture was stirred for 5 hours at roomtemperature. The reaction was quenched by addition of satd NH₄ Cl, andthe mixture was extracted with chloroform. The solvent was dried overMgSO4 and removed under vacuum, and the residue was purified of a columnof silica gel, eluting with 100:1.25:0.025 chloroform:methanol:ammoniumhydroxide. The product was converted into the title compound bytreatment with HCl in ether according to Example 14c. MS (DCI/NH₃) m/e:259 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ: 8.28 (d, J=3.0 Hz, 1H), 8.24 (s,1H), 7.80 (m, 1H), 4.58 (dd, J=11.0, 3.0 Hz, 1H), 4.42 (dd, J=11.4, 5.5Hz, 1H), 3.96 (m, 1H), 3.77 (m, 1H), 3.32-3.23 (m, 1H), 3.05 (s, 3H),2.78 (t, J=7.3, 2H), 2.43-2.38 (m, 1H), 2,26-2.06 (m, 3H), 1.70-1.60 (m,2H), 1.40-1.27 (m, 2H), 0.91 (t, J=7.4 Hz, 3H). Anal. Calc. for C₁₅ H₂₄N₂ O•2 HCl•0.2 ether: C, 56.46; H, 8.40; N, 8.33; Found C, 56.85; H,8.73; N, 7.99. α!²⁵ _(D) =-7.30° (methanol).

EXAMPLE 72 3-((trans-4hydroxy-2-(S)-pyrrolidinyl)methoxypyridinedihydrochloride

72a. CBZ-L-proline, methyl ester

A 12.5 g (47.4 mmol) sample of CBZ-L-proline (Aldrich) was dissolved in250 mL of methanol and 1.7 mL of acetyl chloride was added. The reactionmixture was stirred at room temperature for 16 hours. The solvents wereremoved, the residue was dissolved in CHCl₃, and this solution waswashed with NaHCO₃ solution, dried, filtered and concentrated. Theresidue was purified on a silica gel column, eluting with 1:1 ethylacetate:hexane to give 14 g of the title compound.

72b. O-t-butyldimethylsilyl-CBZ-proline. methyl ester

A 7.5 g sample of the compound from step 72a was dissolved in 140 mL ofDMF and 2.2 g of imidazole was added. The solution was cooled to -23°C., and 4.84 g of t-butyldimethylsilyl chloride was added and stirredfor 1 hour. The volatiles were removed under vacuum, and the residue waspurified on a silica gel column, eluting with 1:2 ethyl acetate:hexaneto give 8.05 g of the title compound.

72c. trans-1-CBZ4(t-butyldimethylsilyloxy)pyrrolidinemethanol

A 3 g sample of the compound from step 72b above was dissolved in 40 mLof THF, and cooled to 0° C. To this solution was added 18.1 mL of DIBAL,and the reaction mixture was warmed to room temperature while stirringfor 3 hours. The reaction was quenched by addition of 10% H₂ SO₄, andthe mixture was extracted with chloroform. The extract was dried,filtered and concentrated. The residue was purified o a silica gelcolumn, eluting with 1:2 ethyl acetate: hexane to give 3 g of the titlecompound.

72d.trans-3-((1-CBZ-4-(t-butyldimethylsilyloxy)-2-(S)-pyrrolidinyl)methoxypyridine

A 2.8 g (10.6 mmol) sample of1-CBZ-4(t-butyldimethylsilyloxy)-pyrrolidinemethanol, from step 72cabove, and 1.5 g (15.8 mmol) of 3-hydroxypyridine were reacted withtriphenylphosphine and DEAD (15.8 mmol each) in 75 mL of THF accordingto the procedure of Example 14a, to give 1.35 g of the title compound.

72e. 3-((trans-4-hydroxy-2-(S)-pyrrolidinyl)methoxy)pyridine

A 1.35 g sample of the compound from step 72d above was dissolved in 9mL of THF and 9.3 mL of tetra-(t-butyl)ammonium fluoride was added. Thereaction mixture was stirred at room temperature for 16 hours, and thevolatiles were removed under vacuum. The residue was purified on silicagel, eluting with 3:1 ethyl acetate:hexane, to give the title compound.

72f. 3-((trans-4-hydroxy-2-(S)-pyrrolidinyl)methoxy)pyridinedihydrochloride

A 350 mg sample of the compound from step 72e above was dissolved in 6mL of ethanol, 35 mg of 10% Pd/C was added, and the reaction mixture wasshaken under 4 atm of H₂ for 15 hours. The catalyst was removed byfiltration, the solvent removed, and the residue was purified bychromatography on silica gel, eluting with 20:1 chloroform:methanol, togive the free base. This compound was treated with HCl in etheraccording to Example 14c to afford the title compound. MS (DCI/NH₃) m/e:195 (M+H)⁺, 212 (M+NH₄)⁺. ¹ H NMR (D₂ O, 300 MHz) δ: 8.46 (d, 1H, J=2.5Hz), 8.37 (d, 1H, J=5.1 Hz), 7.93 (m, 1H), 7.90 (dd, 1H, J=5.5, 8.4 Hz),4.60 (m, 1H), 4.41 (m, 2H), 3.52 (dd, 1H, J=3.7, 2.9 Hz), 3.43 (m, 1H),2.15-2.35 (m, 2H). Anal. Calc. for C₁₀ H₁₄ N₂ O₂ •2.7 HCl: C, 41.04; H,5.75; N. 9.57; Found C, 40.90; H, 5.43; N, 9.48.

EXAMPLE 73 5-methyl-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridinedihydrochloride

73a 5-methyl-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine

A 270 mg (1 mmol) sample of5-bromo-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)-pyridine, from Example 28above, was dissolved in 10 mL of THF, 3.25 mg of Ni(dppp)Cl was added,and the mixture was cooled to 0° C. To this solution was added 0.47 mLof methylmagnesium bromide, then the mixture was stirred at reflux for20 hours. Another 0.2 mL of methylmagnesium bromide was added, and thereaction mixture was stirred for 2 hours. The reaction was quenched byaddition of NH₄ Cl solution, and the mixture was evaporated to dryness.The residue was partitioned between H₂ O and CHCl₃, and the organicextract was dried and concentrated.. The residue was purified bychromatography on silica gel, eluting with 5:1 chloroform:methanol, togive 120 mg of the title compound. MS (DCI/NH₃) m/e: 207 (M+H)⁺. ¹ H NMR(CDCl₃, 300 MHz) δ: 8.13 (d, J=2.7 Hz, 1H), 8.05 (s, 1H), 7.03 (m, 1H),4.04-3.89 (m, 2H), 2.66 (m, 1H), 2.48 (s, 3H), 2.32 (s, 3H), 2.35-2.26(m, 1H), 2.09-1.98 (m, 1H), 1.92-1.68 (m, 3H).

73b. 5methyl-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridinedihydrochloride

The compound from step 73 b above was treated with HCl in etheraccording to Example 14c to afford the title compound. MS (DCI/NH₃) m/e:207 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ: 8.34 (d, J=2.6 Hz, 1H), 8.28 (s,1H), 4.62 (dd, J=11.0, 2.9 Hz, 1H), 4.46 (dd, J=1i.4, 5.9 Hz, 1H), 3.98(m, 1H), 3.76 (m, 1H), 3.27 (m, 1H), 3.05 (s, 3H), 2.50 (s, 3H), 2.41(m, 1i), 2.28-2.05 (m, 3H). Anal. Calc. for C₁₂ H₁₈ N₂ O·2 HCl: C,51.62; H, 7.22; N, 10.03; Found C, 51.54; H, 7.16; N, 9.79.

EXAMPLE 74 3-((trans-4-methoxy-2-(S)-pyrrolidinylmethoxy)pyridinedihydrochloride

74a3-((trans-1-CBZ-4-hydroxy-2-(S)-pyrrolidinyl)methoxy)pyridine A 700mg (1.6 mmol) sample of3-(l-CBZ4(t-butyldimethylsilyloxy)-2-(S)-pyrrolidinylmethoxy)pyridine,prepared as in Example 72d above, was dissolved in 10 mL of THF and 5.0mL (4.8 mmol) of 1M tetra-n-butylammonium 20 fluoride was added. Thereaction mixture was stirred at room temperature for 2 hours, and thesolvent was removed. The residue was purified on a column of silica gel,eluting with 3:1 ethyl acetate:hexane to give 466 mg of the titlecompound. MS (DCI/NH₃) m/e: 328 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ: 8.28(s, 1H), 8.21 (m, 1H), 7.33 (s, 5H), 7.27 (m, 1H), 7.20 (m, 1H), 5.13(s, 2H), 4.59 (m, 1H), 25 4.37 (m, 1H), 3.62 (m, 2H), 3.59 (m, 1H), 3.20(m, 1H), 2.18 (m, 1H).

74b.3-((trans-1-CBZ-4-methoxy-2-(S)-pyrrolidinylmethoxy)pyridine

A 450 mg (1.4 mmol) sample of the compound from step 74a above wasdissolved in 20 mL of THF, and 168 mg (4.2 mmol) of NaH, 180 mg (0.49mmol) of tetra-n-butylammonium iodide and 0.173 mL of methyl iodide wereadded. The reaction mixture was stirred at room temperature for 16hours, and the solvent was removed. The residue was purified on a columnof silica gel, eluting with 1: 1 to 3:1 ethyl acetate:hexane to give 210mg of the title compound.

74c. 3-((trans-4-methoxy-2-(S)-pyrrolidinyl)methoxy)pyridinedihydrochloride

A 158 mg sample of the compound from step 74b above was dissolved inmethanol and hydrogenated in the presence of 15 mg of 5% Pd/C catalystat 1 atm of H₂ for 16 hours. The catalyst was removed by filtration, andthe solvent was removed under pressure to leave 60 mg of free base. Thiscompound was treated with HCl in ether according to Example 14c toafford 45 mg of the title compound. MS (DCI/NH₃) m/e: 209 (M+H)⁺. ¹ HNMR (D₂ O, 300 MHz) δ: 8.52 (d, J=2.6 Hz, 1H), 8.43 (d, J=5.2 Hz, 1H),8.13 (dd, J=8.9, 1.9 Hz, 1 H), 7.94.(dd, J=8.9, 5.5, 1H), 4.64 (dd,J=10.7, 2.9, 1H), 4.46-4.30 (m, 3H), 3.62-3.48 (m, 2H), 3.38 (s, 3H),2.46 (dd, J=14.3, 6.8, 1H), 2.21-2.11 (m, 1i). Calc. for C₁₁ H₁₆ N₂ O₂•2 HCl: C, 46.99; H, 6.45; N, 9.96; Found C, 47.06; H, 6.34; N, 9.81.c!²⁵ _(D) =+32.9° (c=1.0, MeOH).

EXAMPLE 75 5-ethyl-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridinedihydrochloride

75a. 5-ethyl-3-(1-methyl-2-(S)-pyrrolidinylmethoxy pyridine

A 542 mg (2 mmol) sample of5-bromo-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)-pyridine, from Example 28above, was dissolved in 10 mL of THF, 6.6 mg of Ni(dppp)Cl was added,and the mixture was cooled to 0° C. To this solution was added 0.6 mL ofmethylmagnesium bromide, then the mixture was stirred at roomtemperature for 5 hours. The reaction was quenched by addition of NH₄ Clsolution, and the mixture was extracted with CHCl₃. The organic extractwas dried and concentrated.. The residue was purified by chromatographyon silica gel, eluting with 100: 1.25:0.025 chloroform:methanol:ammonium hydroxide, to give 40 mg of the title compound. MS(DCI/NH₃) m/e: 221 (M+H)⁺. ¹ H NMR (CDCI₃, 300 MHz) δ: 8.16 (d, J=2.4Hz, 1H), 8.08 (d, J=1.2 Hz, 1H), 7.06 (t, J=2.4 Hz, 1H), 4.02 (dd,J=9.3, 5.4 Hz, 1H), 3.92 (dd, J=9.0, 6.0 Hz, 1H), 3.12 (m, 1H),2.70-2.59 (m, 3H), 2.49 (s, 3H), 2.32 (m, 1H), 2.04 (m, 1H), 1.93-1.68(m, 3H), 1.25 (t, J=7.80, 3H4).

75b. 5-ethyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride

The compound from step 75 b above was treated with HCl in etheraccording to Example 14C to afford the title compound. MS (DCI/NH₃) m/e:221 (M+H)⁺. ¹ H NMR (D₂ O,300 MHz) δ: 8.22 (d, J=6.0, 2H), 7.65 (s, 1H),4.48 (dd, J=12.0, 3.0, 1H), 4.21 (m, 1H), 3.94 (m, 1H), 3.77 (m, 1H),3.28 (m, 1H), 3.05 (s, 3H), 2.76 (q, 2H), 2.45 (m, 1H), 2.28-2.03 (m,3H), 1.24 (t, J=4.5 Hz, 3H). Anal. Calc. for C₁₃ H₂₀ N₂ O•2 HCl: C,53.24; H, 7.56; N, 9.55; Found C, 53.53; H, 7.77; N, 9.20.

EXAMPLE 76 3-(2-(R)-pyrrolidinylmethoxy)quinoline dihydrochloride

76a. 3-((1-BOC-2-(R)-pyrrolidinyl)methoxy)quinoline

A 2.77 g sample of (R)-1-t-butoxycarbonyl-2-pyrrolidinemethanol and 3 gof 3-hydroxyquinoline were reacted with triphenylphosphine and DEAD in100 mL of THF according to the procedure of Example 14a, to give 2.5 gof the title compound. MS (DCI/NH₃) m/e 329 (M+H)⁺. ¹ H NMR (CDCl₃, 300MHz) δ: 8.67 (d, J=3 Hz 1H), 8.4 (d, J=7 Hz, 1H), 7.72 (dd, J=7, 1 Hz1H), 7.56-7.40 (m, 3H), 4.24-3.94 (m, 3 H), 3.42 (bs 2H), 2.11-1.94 (m3H), 1.92-1.86 (m 1H), 1.48 (s 9H)

76b. 3-(2-(R)-pyrrolidinylmethoxy)quinoline dihydrochloride

A 2.5 g sample of the compound from step 76a above was dissolved in 8 mLof methylene chloride and cooled in an ice bath. To this solution wasadded 8 mL of trifluoracetic acid, and the reaction mixture was stirredfor 1 hour. Water was added, and the layers were separated. The organiclayer was extracted with 2M HCl. The aqueous layers were combined andextracted with ether. The aqueous solution was then adjusted to pH 10with K₂ CO₃ and extracted with methylene chloride. The solvent wasremoved, and the residue was purified by chromatography on silica gel.The compound was treated with HCl in ether according to Example 14c toafford the title compound. MS (DCI/NH₃) m/e 229 (M+H)⁺, 246 (M+NH₄)⁺. ¹H NMR (D₂ O, 300 MHz) δ: 8.94(d J=3 Hz, 1H), 8.47 (d J=3 Hz, 1H), 8.14(dd J=8, 1 Hz 2H), 7.98-7.84 (m, 2H), 4.69 (dd, J=11, 4 Hz 1H), 4.48(dd, J=11,7Hz 1H), 4.23 (m, 1H), 3.46 (t, J=7, 2H), 2.40-2.30 (m, 1H),2.28-1.97 (m, 3H). Anal. Calc. for C₁₄ H₁₆ N₂ O•2 HCl: C, 55.82; H,6.02; N, 9.30; Found C, 55.63; H, 6.08; N, 9.07.

EXAMPLE 77 5-n-propyl-3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridinedihydrochloride

To a 1.08 g (4 mmol) sample of5bromo-3-((1-methyl-2-(S)-pyrrolidinyl)-methoxy)pyridine, prepared as inExample 56a above, dissolved in 30 mL of dry THF and cooled to 0° C. wasadded 6.0 mL of n-propylmagnesium chloride and 13.0 mg of Ni(dppp)Cl,and the reaction mixture was stirred for 5 hours at room temperature.The reaction was quenched by addition of satd NH₄ Cl, and the mixturewas extracted with chloroform. The solvent was dried over MgSO₄ andremoved under vacuum, and the residue was purified of a column of silicagel, eluting with 100: 1.25:0.025 chloroform:methanol:ammoniumhydroxide. The product was converted into the title compound bytreatment with HCl in ether according to Example 14c. MS (DCI/NH₃) m/e:235 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ: 8.28 (s, 1H), 8.23 (s, 1H), 7.78(m, 1H), 4.58 (dd, J=11.4, 3.7 Hz, 1H), 4.42 (dd, J=11.1, 5.9 Hz, 1H),3.95 (m, 1H), 3.77 (m, 1H), 3.31-3.25 (m, 1H), 3.05 (s, 3H), 2.74 (t,J=7.3 Hz, 2H), 2.48-2.36 (m, 1H), 2.25-2.06 (m, 3H), 1.68 (m, 2H), 0.91(t, J=7.4 Hz, 3H). Anal. Calc. for C₁₄ H₂₂ N₂ O•1.9 HCl•0.3 ether. C,56.03; H, 8.22; N, 8.60; Found C, 56.35; H, 8.48; N, 8.73. α!²⁵ _(D)=-3.05° (methanol).

EXAMPLE 78 3-((cis-4-fluoro-1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridinedihydrochloride

78a. 3-((cis-4-fluoro-1-methyl-2-(S)-pyrrolidinyl)methoxypyridine

A 100 mg (0.5 mmol) sample of3-((trans-1-methyl-4-hydroxy-2(S)-pyrrolidinyl)methoxy)pyridine, fromExample 23 above, above was dissolved in 10 mL of methylene chloride andcooled to -78° C. To this was added 0.165 mL (1.25 mmol) of DAST, andthe mixture was stirred for 4 hours while allowing the reaction mixtureto warm to room temperature. The reaction was quenched by addition ofsatd NaHCO₃ solution, and the mixture was extracted with chloroform. Thesolvent was removed, and the residue was purified by chromatography onsilica gel, eluting with 20:1 CHCl₃ :methanol, to give 30 mg of titlecompound.

78b. 3-((cis-4-fluoro-1-methyl-2-(S)-pyrrolidinyl)methoxypyridinedihydrochloride

The compound from step 78a above was treated with HCl in ether accordingto Example 14c to afford 20 mg of the title compound. MS (DCI/NH₃) m/e:211 (M+H)⁺. ¹ H NMR (CD₃ OD, 300 MHz) δ: 8.77 (d, J=2.6 Hz, 1H), 8.57(d, J=5.5 Hz, 1H), 8.37 (m, 1H), 8.08 (m, 1H), 5.60-5.46 (m, 1H),4.72.(m, 1H), 4.58 (m, 1H), 4.21 (m, 1H), 4.04 (m, 1H), 3.65-3.47 (m,1H), 3.19 (s, 3H), 3.02-2.80 (m, 1H), 2.43-2.28 (m, 1H). Anal. Calc. forC₁₁ H₁₅ N₂ OF•2.4 HCl•0.2-H₂ O: C, 43.84; H, 5.95; N, 9.29; Found C,43.47; H, 5.88; N, 8.98

EXAMPLE 79 3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridazinedihydrochloride

A 92.8 mg (0.27 mmol) sample of 3-((1-methyl-2-(S)-5pyrrolidinyl)methoxy)-6-chloropyridazine fumarate, from Example 12above, was dissolved in 10 mL of a 4:1 mixture of ethyl acetate:ethanol,and 0.124 mL (0.89 mmol) of triethylamine and 5 mg of 10% Pd/C wereadded. The mixture was hydrogenated under 1 atm of H₂ for 30 minutes,then the catalyst was removed by filtration. The solvents were removedunder vacuum, To the residue was added 20 mL of satd NaHCO₃ solution,and the mixture was extracted with methylene chloride. The solution wasdried over MgSO₄ and taken to dryness, the residue was azeotroped withethanol several times to remove residual triethylamine. The residue wastreated with HCl in ether according to Example 14c to afford 40 mg ofthe title compound. mp 176-177° C. MS (DCI/NH₃) m/e: 194 (M+H)⁺. ¹ H NMR(D₂ O, 300 M) δ: 8.89 (dd, 1H, J=4.6, 1.3 Hz), 7.75 (dd, 1H, J=9.0, 4.6Hz), 7.38 (dd, 1H, J=9.0, 1.3 Hz), 4.84 (dd, 1H, J=12.3, 3.1 Hz), 4.67(dd, 1H, J=12.3, 6.1 Hz), 3.98 (m, 1H), 3.76 (m, 1H), 3.26 (m, 1H), 3.04(s, 3H), 2.41 (m, 1H), 2.23 (m, 1H). Anal. Calc. for C₁₀ H₁₇ Cl₂ N₃O•0.3 HCl: C, 43.34; H, 6.29; N, 15.11; Found C, 43.23; H, 6.19; N,14.78

EXAMPLE 80 5-chloro-3-((1-methyl-2-(S)-azetidinyl)methoxy)pyridinedihydrochloride

80a. 5-chloro-3-((1-methyl-2-(S)-azetidinyl)methoxy)pyridine

A 500 mg sample of5-chloro-3-(N-t-butoxycarbonyl-2-(S)-azetidinylmethoxy)pyridine,prepared as in Example 39a above, was dissolved in 3 mL of 37% HCHO and1.5 mL of HCOOH, and the reaction mixture was stirred at 100° C. for 40minutes. The reaction was quenched by addition of H₂ O The mixture wasadjusted to pH 7 with NaHCO₃ and extracted with methylene chloride, theextract was dried over MgSO₄, and the solvent was removed to give thetitle compound (181 mg). MS (DCI/NH₃) m/e: 213/215 (M+H)⁺. ¹ H NMR(CDCl₃, 300MHz) δ: 8.22 (d, J=2.5 Hz, 1H), 8.17 (d, J=1.9 Hz, 1H), 7.23(dd, J=2.5, 1.9 Hz, 1H), 4.01 (d, J=5.1 Hz, 2H), 3.52-3.44 (m, 1H),3.45-3.35 (m, 1H), 2.94-2.83 (m, 1H), 2.41 (s, 3H), 2..15-2.04 (m, 2H).

80b. 5-chloro-3-((1-methyl-2-(S)-azetidinyl)methoxypyridinedihydrochloride

The compound of step 80a was treated with HCl in ether according toExample 14c to afford 78 mg of the title compound. mp 176-177° C. MS(DCI/NH₃) m/e: 213/215 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ: 8.28 (d, J=2.5Hz, 1H), 8.25 (d, J=1.9 Hz, 1H), 7.63 (dd, J=2.5, 1.9 Hz, 1H), 4.90-469(m, 2H), 4.55-4.38 (m, 1H), 4.35-4.22 (m, 1H), 4.06-3.95 (m, 1H), 2.99(s, 3H), 2.75-2.55 (m, 2H). Anal. Calc. for C₁₀ H₁₄ Cl₂ N₂ O•0.7 HCl•0.5H₂ O: C, 42.34; H, 5.58; N, 9.88; Found C, 42.46; H, 5.62; N, 9.93. α!²⁵_(D) =-20.0° (c=0.35, methanol).

EXAMPLE 81 2-methyl-3-(2-(R)-azetidinylmethoxy)pyridine dihydrochloride

Replacing the 1-BOC-2-(S)-azetidinemethanol of Example 29a with1-BOC-2-(R)-azetidinemethanol, from Example 62b, and carrying thereactions forward as in Example 29, except using di-t-butyl dicarbonatein place of DEAD, the free base of the title compound was prepared as ahygroscopic oil. This compound was treated with HCl in ether accordingto Example 14c to afford the title compound. MS (DCI/NH₃) m/e: 179(M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ: 8.16 (d, J=5.5 Hz, 1H), 7.79 (d,J=8.5, 1H), 7.62 (dd, J=8.5, 5.5 Hz, 1H), 5.00 (m, 1H), 4.57-4.47 (m,2H), 4.24 (m, 2H), 4.24-4.12 (m, 2H), 2.78-2.71 (m, 2H). Anal. Calc. forC₁₀ OH₁₆ Cl₂ N₂ O•0.5 H₂ O: C, 46.17; H, 6.59; N, 10.77; Found C, 45.93;H, 6.61; N, 10.63. α!²³ _(D) =-5.85° (c=0.21, methanol).

EXAMPLE 82 3-((1-allyl-2-(S)-pyrrolidinyl)methoxy)pyridinedihydrochloride

82a. 3-((1-allyl-2-oxo-5-(S)-pyrrolidinyl)methoxypyridine

To a solution of 3-((2-oxo-5-(S)-pyrrolidinyl)methoxy)pyridine, fromExample 22a (450 mg, 2.34 mmol), in 10 mL of anhydrous THF at 0° C. wasadded NaH (80% dispersion, 186 mg, 2.68 mmol) was added, and thereaction mixture was stirred for 20 minutes at this temperature. Thereaction was then warmed to room temperature, and allyl bromide (425 mg,3.51 mmol) was added via syringe. After starting material was consumed,water was added to quench the reaction. The desired compound wasextracted from the aqueous phase with ethyl acetate and chloroform. Theorganic layer was dried over MgSO₄, then taken to dryness. The residuewas purified by silica gel flash chromatography (5% MeOH/CHCl₃) to give450 mg of the title compound. MS (DCI/NH₃) m/e: 233 (M+H)⁺. ¹ H NMR (D₂O, 300 MHz) δ: 8.37-8.26 (m, 2H), 7.38-7.29 (m, 2H), 5.83-5.69 (m, 1H),5.26-5.13 (m, 2H), 4.35-4.24 (m, 1H), 4.16-3.96 (m, 3H), 3.77-3.67 (m,1H), 2.68-2.54 (m, 1H), 2.50-2.38 (m, 1H), 2.36-2.20 (m, 1H), 2.09-1.96(m, 1H).

82b. 3-((1-allyl-2-(S)-pyrrolidinyl)methoxy)pyridine dihydrochloride

To a solution of 120 mg of the compound from step 82a above in 2 mL ofTHF was added 0.52 mL of LAH in ether, and the mixture was stirred atroom temperature for 3 hours. Quenching with H₂ O, 40% NaOH and H₂ O, inthat order, was followed by stirring for 1 hour. The mixture wasfiltered, and the solvent was evaporated. The residue was purified bychromatography on silica gel, eluting with 10:1 chloroform:methanol. Thecompound of step 81b was treated-with HCl in ether according to Example14c to afford the tide compound. ¹ H NMR (D₂ O, 300 MHz) δ: 8.54 (d,J=2.6 Hz, 1H), 8.45 (d, J=5.5, 1H), 8.17 (m, 1H), 7.97 (dd, J=8.8, 5.6Hz, 1H), 6.07-5.93 (m, 1H), 5.98-5.93 (m, 2H), 4.64 (dd, J=3.3, 11 Hz,1H), 4.49 (dd, 1H, J=6.3, 11 Hz), 4.20-4.06 (m, 2H), 3.86 (dd, J=7.4, 13Hz, 1H), 3.79-3.69 (m, 1H), 3.42-3.25 (m, 1H), 2.50-2.34 (m, 1H),2.28-2.02 (m, 3H). Anal. Calc. for C₁₃ H₂₀ Cl₂ N₂ O•0.5 H₂ O: C, 52.01;H, 7.05; N, 9.33; Found C, 52.00; H, 7.19; N, 9.49.

EXAMPLE 833-((trans-4-hydroxymethyl-1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridinedihydrochloride

83a.3-((trans-4hydroxymethyl-1-methyl-2(S)-pyrrolidinyl)methoxy)pyridine

A 1.0 g (4.2 mmol) sample of3-((-1-methyl-4-hydroxymethyl-5-oxo-2(S)-pyrrolidinyl)methoxy)pyridine,from step 48a above, was dissolved in 15 mL of anhydrous THF, 12.7 mL ofBH₃ was added, and the mixture was heated at reflux for 2.5 hours. Thereaction was quenched with methanol, the solvent was evaporated, and theresidue was dissolved in anhydrous ethanol. Cesium fluoride was added,and the resultant solution was stirred under reflux for 16 hr.Evaporation of the solvent and purification of the residue on a silicagel column, eluting with 100:8 to 10: 1 chloroform:methanol gave 600 mgof the title compound as a mixture of cis and trans product.

83b.3-((trans-4-hydroxymethyl-1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridinedihydrochloride

The trans-compound from step 83a was treated with HCl in ether accordingto Example 14c to afford the title compound. mp 151-154° C. MS (DCI/NH₃)m/e: 223 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ: 8.49 (d, 1H, J=3 Hz), 8.39(dd, 1H, J=1, 5 Hz), 8.0 (m, 1H), 7.82 (dd, 1H, J=5, 8 Hz), 4.68-4.60(m, 1H), 4.54-4.43 (m, 1H), 4.10-3.95 (m, 1H), 3.76-3.60 (m, 2H),3.50-3.40 (m, 1H), 3.40 (s, 3H), 2.90-2.77 (m, 1H), 2.60-2.46 (m, 1H),2.35-2.13 (m, 1H), 1.98-1.85 (m, 1H). Anal. Calc. for C₁₂ H₂₀ N₂ O₂ Cl₂: C, 48.82; H, 6.82; N, 9.49; Found C, 48.82; H, 6.68; N, 9.26.

EXAMPLE 84 5-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyrimidinedihydrochloride

To a sample of 1-methyl-2(S)-pyrrolidinemethanol (Aldrich, 16.81 mmol)in 2 mL of DMF was added 0.74 g of NaH (60% dispersion in oil, 18.49mmol) and 2.68 g (16.81 mmol) of 5-bromopyrimidine. The reaction mixturewas stirred at 60° C. for 18 hours, then poured onto ice. The mixturewas diluted with brine, and extracted with methylene chloride. Theextract was dried over MgSO₄, and the solvent was removed. The residuewas chromatographed on silica gel, eluting with 20:1chloroform:methanol. The compound was then taken up in methylenechloride, HCl in ether was added, and the volatiles removed undervacuum. The salt was recrystallized from acetonitrile/ether to afford822 mg of the title compound. mp >160° C. (dec). MS (DCI/NH₃) m/e: 194(M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ: 8.88 (s, 1H-), 8.65 (s, 2H), 4.64(dd, J=11.2, 3.1 Hz, 1H), 4.47 (m, 1H), 3.95 (m, 1H), 3.77 (m, 1H), 3.29(m, 1H), 3.05 (s, 3H), 2.43 (m, 1H), 2.24 (m, 1H), 2.11 (m, 2H). Anal.Calc. for C₁₀ H₁₅ N₃ OCl₂ : C, 45.13; H, 6.44; N, 15.79; Found C, 45.13;H, 6.74; N, 15.69. α!²⁵ _(D) =-2.6° (c=0.57, methanol).

EXAMPLE 85 3-(2-(S)-azetidinylmethoxy)-6-chloropyridazine hydrochloride

A 811 mg sample of 3-(1-BOC-2(S)-azetidinylmethoxy)-6-chloro-pyridazine,prepared as in Example 13a above, was dissolved in 10 mL of satd HCl inethanol cooled to 0° C., and the reaction was stirred at roomtemperature for 16 hours. The solvent was removed under vacuum, and theoily residue was dried under high vacuum for 4 hours to provide a solid.The solid was triturated with ether, collected, and recrystallized threetimes from ethanol/ether to give 118 mg of the title compound. mp150-151° C. MS (DCI/NH₃) m/e: 200 (M+H)⁺. ¹ H NMR (DMSO 4,300 MHz) δ:9.31 (br s, 1H), 7,87 (d, J=9.2 Hz, 1H), 7.44 (d, J=9.2 Hz, 1H),4.84-4.63 (m, 3H), 3.98-3.83 (m, 2H), 2.59-2.36 (m, 2H). Anal. Calc. forC₈ H₁₁ N₃ OCI₂ : C, 40.70; H, 4.70; N, 17.80; Found C, 40.58; H, 4.59;N, 17.58.

EXAMPLE 86 3-((1-methyl-2-(S)-azetidinyl)methoxy-6-chloropyridinehydrochloride

A 628 mg (2.67 mmol) sample of5-(2-(S)-azetidinylmethoxy)-2-chloropyridine dihydrochloride, preparedas in Example 52 above, was dissolved in 4 mL of water, and 1 mL ofacetic acid, 2 mL of 37% HCHO, and 500 mg of NaCNBH₄ were added. Thereaction was stirred until the reaction was complete, with addition ofacetic acid as necessary to maintain the acidity at approximately pH 5.Then 2 mL of 2N HCl was added, and the mixture was extracted with ethylacetate. The aqueous fraction was made basic with K₂ CO₃ and extractedwith chloroform. The extract was dried over MgSO₄, concentrated, and theresidue was purified by chromatography on silica gel, eluting with 2% to5% methanol in chloroform to give 210 mg of base. This compound wasconverted to the salt by treatment with HCl in ethanol, to give 222 mgof the title compound. mp 108-110° C. MS (DCI/NH₃) m/e: 213 (M+H)⁺. ¹ HNMR (D₂ O, 300 MHz) δ: 8.16 (d, J=3.3 Hz, 1H), 7.56 (dd, J=8.8, 3.3 Hz,1H), 7.48 (d, J=8.8 Hz, 1H), 4.84-4.73 (m, 1H), 4.52-4.39 (m, 2H),4.27-4.19 (m, 1H), 4.05-3.96 (m, 1H), 2.97 (s, 3H), 2.73-2.55 (m, 2H).Anal. Calc. for C₁₀ H₁₄ N₂ OCl₂ •).2 HCl: C, 46.84; H, 5.58; N, 10.92;Found C, 47.09; H, 5.66; N, 10.91.

EXAMPLE 873-((trans-4-methanesulfonyloxy-1-methyl-2(S)-pyrrolidinyl)methoxy)pyridinedihydrochloride

88a.3-((trans-1-methyl-4methanesulfonyloxy-5-oxo-2(S)-pyrrolidinyl)-methoxy)pyridine

A 570 mg (2.6 mmol) sample of3-((trans-1-methyl)hydroxy-5-oxo-2(S)-pyrrolidinyl)methoxy)pyridine,prepared as in Example 23a, was dissolved in 17 mL of methylenechloride, and 0.72 mL (5.2 mmol) of triethylamine, a catalytic amount ofDMAP and 0.302 mL (3.9 mmol) of methanesulfonyl chloride were added. Thereaction mixture was stirred at room temperature for 16 hours thenquenched by the addition of H₂ O. The solvent was stripped from themixture under vacuum, NaHCO₃ was added, and the mixture was extractedwith chloroform. The solvent was removed, and the residue was purifiedby chromatography on silica gel to give 780 mg of title compound.

88b.3-((trans-1-methyl-4-hydroxy-5-oxo-2(S)-pyrrolidinyl)methoxy)pyridinedihydrochloride

A sample of the compound from step 88a was reacted with borane in THFaccording to the method of Example 23b, followed by treatment of theintermediate with cesium fluoride in ethanol for 16 hours at roomtemperature. Evaporation of the solvent provided a residue which waspurified on a silica gel column to give 50 mg of base. This compound wasconverted to the salt by treatment with HCl in ethanol. mp 65-67° C. MS(DCI/NH₃) m/e: 287 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ: 8.44 (d, J=2.6 Hz,1H), 8.34 (m, 1H), 7.84 (m, 1H), 7.70 (dd, J=8.9, 5.2 Hz, 1H), 5.62 (m,1H), 4.69 (dd, J=11.8, 2.9 Hz, 1H), 4.52 (m, 1H), 4.41-4.33 (m, 1H),4.19 (dd, J=14.0, 4.8 Hz, 1H), 3.76 (m, 1H), 3.33 (s, 3H), 3.17 (s, 3H),2.80-2.59 (m, 2H). Anal. Calc. for C₁₂ H₁₈ N₂ O4Ψ1.5 HCl: C, 42.26; H,5.76; N, 8.24; Found C, 42.59; H, 5.60; N, 8.10.

EXAMPLE 886-hydroxymethyl-3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridinedihydrochloride

88a 6-acetyloxymethyl-3-((1-BOC-2-(S)-pyrrolidinyl)methoxy)pyridine

A sample of (S)-1-t-butoxycarbonyl-2-pyrrolidinemethanol (1.64 g, 8.18mmol, prepared as in Example 15a above) and 1.05 g (6.29 mmol) of6-acetyloxymethyl-3-hydroxypyridine, prepared as described by Deady andDayhe, Aust. J. Chem., 2565:36 (1983), were reacted withtriphenylphosphine and DEAD (8.18 mmol each) in 25 mL of THF accordingto the procedure of Example 14a. Workup gave 1.90 g of title compound.MS (DCI/NH₃) m/e: 309 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ: 8.32-8.28 (m,1H), 7.33-7.25 (m,.2H), 5.15 (s, 2H), 4.30-3.90 (m, 2H), 3.65-3.25 (m,3H), 2.13 (s, 3H), 2.10-1.80 (m, 3H), 1.49 (s, 9H).

88b. 6-hydroxymethyl-3-((1-BOC-2-(S)-pyrrolidinyl)methoxy)pyridine

To a solution of 1.0 g of the compound from step 88b in methanol wasadded a solution of 342 mg of KOH in 1 mL of methanol while cooling in awater bath. The reaction mixture was stirred at room temperature for 30minutes, then neutralized an concentrated. The residue was purified bychromatography on silica gel, eluting with 1:1 ether hexane and ethylacetate to give 1.22 g of title compound. MS (DCI/NH₃) m/e: 351 (M+H)⁺.¹ H NMR (CDCl₃, 300 MHz) δ: 8.27 (d, J=3.0 Hz, 1H), 7.28 (dd, J=9.3, 3.0Hz, 1H), 7.16 (d, J=9.3 Hz, 1H), 4.70 (s, 2H), 4.25-3.80 (m, 3H),3.48-3.30 (m, 3H), 2.10-1.83 (m, 3H), 1.49 (s, 9H).

88c. 6-hydroxymethyl-3-((1-methyl-2-(S)-pyrrolidinylmethoxy pyridine

A 669 mg sample of the compound of step 88b above was stirred with 2 mLof 37% HCHO and 1 mL of HCOOH, and the reaction mixture was stirred at100° C. for 40 minutes. The reaction was quenched by addition of H₂ OThe mixture was adjusted to pH 7 with NaHCO₃ and extracted withmethylene chloride, the extract was dried over MgSO₄, and the solventwas removed to give the title compound MS (DCI/NH₃) m/e: 223 (I+H)⁺. ¹ HNMR (CDCl₃, 300 MHz) δ: 8,28 (d, J=3.0 Hz, 1H), 7.24 (dd, J=9.3, 3.0 Hz,1H), 7.17 (d, J=9.3 Hz, 1H), 4.71 (s, 2H), 4.05-3.98 (m, 1H), 3.97-3.91(m, 1H), 3.17-3.08 (m, 1H), 2.73-2.63 (m, 1H), 2.51 (s, 3H), 2.38-2.27(m, 1H), 2.11-1.68 (m, 4H).

88d. 6-hydroxymethyl-3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridinedihydrochloride

A 60 mg sample of the compound of compound from step 88c was treatedwith HCl in ether according to Example 14e to afford 66 mg of the titlecompound. MS (DCI/NH₃) m/e: 223 (M+H)⁺. ¹ H NMR (D2O,300 Mz) δ: 8.38 (d,J=3.0 Hz, 1H), 7.92 (dd, J=9.3, 3.0 Hz, 1H), 7.74 (d, J=9.3 Hz, 1H),4.85 (s, 2H), 4.634.55 (m, 1H), 4.01-3.90 (m, 1H), 3.82-3.73 (m, 1H),3.32-3.21 (m, 1H), 3.04 (s, 3H), 2.47-2.03 (m, 4H). Anal. Calc. for C₁₂H₂₀ Cl₂ N₃ •0.4 H₂ O: C, 47.66; H, 6.93; N, 9.26; Found C, 47.58; H,7.05; N, 9.23. α!²⁵ _(D) =-4.4° (c=0.50, methanol).

EXAMPLE 89 3-((trans-1,5-dimethyl-2-(S)-pyrrolidinyl)methoxy)pyridinehydrochloride

89a. 3-((1,5-dimethyl-2-(S)-pyrrolidinyl)methoxy)pyridine

A 1.24 g (6.0 mmol) sample of3-(1-methyl-2-oxo-5-(S)-pyrrolidinylmethoxy)-pyridine, prepared as inExample 22b above, was dissolved in 50 mL of ether and cooled to -78° C.To this solution was added 4.71 mL (6.6 mmol) of methyl lithium, and thesolution was warmed to room temperature and stirred for 2 hours. Thesolution was cooled to 0° C., 66 mL of a 1M solution of LAlH₄ was added,and the reaction mixture was stirred for 2 hours at room temperature.The reaction was quenched by addition of 1 mL of methanol, the solventsremoved, and the residue purified by chromatography on silica gel,eluting with 200:1 to 100:1 chloroform:methanol. MS (DCI/NH₃) m/e: 207(M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ: 83.4-8.30 (m, 1H), 8.24-8.17 (m,1H), 7.25-7.27 (m, 2H), 4.08-4.03 (m, 1H), 3.93-3.87 (m, 1H), 2.83-2.73(m, 1H), 2.43 (s, 3H), 2.43-2.35 (m, 1H), 2.03-1.82 (m, 2H), 1.70-1.40(m, 2H), 1.13 (d, J=6.7 Hz, 3H).

89b. 3-((trans-1,5-dimethyl-2-(S)-pyrrolidinyl)methoxy)pyridinedihydrochloride

A 25 mg sample of the compound of compound from step 89a was treatedwith HCl in ether according to Example 14c to afford 37 mg of the titlecompound. MS (DCI/NH₃) m/e: 207 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ:8.42-8.38 (m, 1H), 8.34-8.28 (m, 11), 7.80-7.76 (m, 1H1), 7.67-7.63 (m,1H), 4.60-4.54 (m, 11H), 4.47-4.41 (m, 1H), 4.03-3.95 (m, 1H), 3.62-3.52(m, 1H), 3.03 (s, 3H), 2.40-2.30 (m, 2H), 2.13-2.03 (m, 1H1), 1.93-1.80(m, 1H), 1.47 (d, J=6.7 Hz, 3H). α!²⁵ _(D) =+15.420 (c=0.50, methanol).Anal. Calc. for C₁₂ H₁₈ N₂ O•0.40 HCl: C, 49.06; H, 7.00; N, 9.54;Found: C, 49.22; H, 6.47; N, 9.69.

EXAMPLE 90 3-((cis-4-cyano-1-methyl-2(S)-pyrrolidinyl)methoxy)pyridinedihydrochloride

90a 3-((cis-4-cyano-1-methyl-2(S)-pyrrolidinyl)methoxy)pyridine

To a solution of 300 mg (1.05 mmol) of3-((trans-1-methyl-4-methanesulfonyloxy-5-oxo-2(S)-pyrrolidinyl)-methoxy)pyridine,prepared as in Example 88a above, dissolved in 7 mL of 6:1 DMF:H₂ O wasadded 0.51 g (10.5 mmol) of NaCN, and the reaction mixture was heated at100° C. for 5 hours. The reaction mixture was cooled, diluted withwater, and extracted with chloroform. The extract was dried over MgSO₄and concentrated. The residue was purified on a silica gel column,eluting with 100:2 chloroform:methanol, to give 80 mg of the titlecompound.

90b 3-((cis-4-cyano-1-methyl-2(S)-pyrrolidinylmethoxy)pyridinedihydrochloride

The compound of compound from step 90a was treated with HCl in etheraccording to Example 14c to afford 75 mg of the title compound, mp220-222° C. MS (DCI/NH₃) m/e: 218 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ:8.46 (d, J=2.9 Hz, 1H), 834 (m, 1H), 7.86 (m, 1H), 7.70 (m, 1H), 4.62(m, 1H), 4.49 (m, 1H), 4.04 (m, 2H), 3.85 (m, 1H), 3.66 (m, 1H), 3.05(s, 3H), 2.91 (m, 1H), 2.55 (m, 1H).

α!²⁵ _(D) =+15.14° (c=0.50, methanol). Anal. Calc. for C₁₂ H₁₅ N₃ O•2HCl•0.6 H₂ O: C, 47.88; H, 6.09; N, 13.96; Found C, 47.70; H, 5.95; N,14.14.

EXAMPLE 913-((cis-5-n-butyl-1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridinedihydrochloride

91 a. 3-((cis-5-n-butyl-1-methyl-2-(S)-pyrrolidinyl)methoxy pyridine

A 1.24 g (6.0 mmol) sample of3-(1-methyl-2-oxo-5-(S)-pyrrolidinylmethoxy)-pyridine, prepared as inExample 22b above, was dissolved in 10 mL of THF and cooled to -75° C.To this solution was added 6.0 mL (12 mmol) of 2 M methyl lithium, andthe solution was warmed to room temperature, then stirred for 44 hours.Two mL of methanol were added, and the mixture concentrated undervacuum. Another 10 mL of methanol was added, followed by 65.6 mg ofNaBCNH₃ and a trace of bromocresol green indicator. HCl (4M) was addedslowly until the solution remained a yellow color, then the reactionmixture was stirred for 1 hour. The mixture was then adjusted to basicpH with satd NaHCO₃, concentrated, and extracted with ethyl acetate. Theextract was dried, concentrated and chromatographed on silica gel togive 86 mg of title compound MS (DCI/NH₃) m/e: 248 (M+H)⁺. ¹ H NMR(CDCl₃, 300 MHz) δ: 8.33-8.31 (m, 1H), 8.23-8.19 (m, 1H), 7.23-7.19 (m,2H), 4.11-4.04 (m, 1H), 3.93-3.86 (m, 1H), 2.87-2.77 (m, 1H), 2.46 (s,3H), 2.40-2.27 (m, 1H), 2.05-1.20 (m, 10H), 0.92 (t, J=6.0 Hz, 3H).

91b. 3-((cis-5-n-butyl-1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine

The compound from step 91a was treated with HCl in ether according toExample 14c to afford 106 mg of the tide compound. MS (DCI/NH₃) m/e: 248(M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ: 8,37-8.33 (m, 1H), 8.27-8.24 (m, 1H),7.67-7.61 (m, 1H), 7.57-7.67 (m, 1H), 4.57-4.52 (m, 1H), 4.4-4.37 (m,1H), 4.03-3.93 (m, 1H), 3.53-3.42 (m, 1H), 3.05 (s, 3H), 2.50-30 (m,1H), 2.05-1.20 (m, 10H), 0.91 (t, J=6.0 Hz, 3H). a!²⁵ _(D) =+24.8°(c=0.60, methanol).

EXAMPLE 923-((cis-4-fluoromethyl-1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridinedihydrochloride

92a. 3-((cis-4fluoromethyl-1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine

A 1.57 g (7.1 mmol) sample of3-((4-hydroxymethyl-1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine,prepared as described in Example 48b above, was dissolved in 40 mL ofmethylene chloride, and the solution was cooled to -78° C. To thissolution was added 2.80 mL (21.2 mmol) of DAST, then the solution wasstirred at -35° C. for 1.5 hours. The reaction mixture was warmed toroom temperature, and the reaction was quenched by the addition of satdNaHCO₃. The mixture was extracted with chloroform, the solvent wasremoved, and the residue was purified on a silica gel column, elutingwith 100:2 chloroform:methanol to 10:1:0.02 chloroform:methanol:ammonia,to give 120 mg of the title compound.

92a. 3-((cis-4-fluoromethyl-1-methyl-2-(S)-pyrrolidinylmethoxy pyridinedihydrochloride

The compound from step 92a was treated with HCl in ether according toExample 14c to afford the title compound. MS (DCI/NH₃) m/e: 225 (M+H)⁺.¹ H NMR (D₂ O, 300 MHz) δ: 8.63 (d, J=0.9 Hz, 1H), 8.44 (m, 1H), 7.97(m, 1H), 4.64-4.43 (m, 5H), 3.49 (m, 1H), 3.31 (m, 1H), 2.92 (s, 3H),2.90 (m, 1H), 2.41 (m, 1H), 1.63 (m, 1H). 2D NOE data are consitent withthe cis configuration. Anal. Calc. for C₁₂ H₁₇ N₂ OF•2 HCl: C, 48.50; H,6.44; N, 9.43; Found C, 48.22; H, 6.65; N, 9.26. α!²⁵ _(D) -+5.8320(methanol).

EXAMPLE 93 3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)-5-nitro-pyridinedihydrochloride

93a 3,5-dinitropridine

A sample of 2-chloro-3,5-dinitropyridine is dissolved in methanol,hydrazine is added, and the reaction mixture is stirred for 16 hours.The solvent is removed, the residue is dissolved in water, silveracetate is added, and the mixture is heated at reflux for 3 hours. Thesolution is adjusted to a basic pH, and product is extracted with CHCl₃.

93b. 3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)-5-nitro-pyridinedihydrochloride

A sample of 3,5-dinitro pyridine from step 93a above is reacted with(S)-(-)-1-methyl-2-pyrrolidinemethanol according to the procedure ofExample 3a, and the product is converted into the title compound bytreatment with HCl in ether according to Example 14c.

EXAMPLE 94 5-Amino-3-(1-methyl-2(S)-pyrrolidinylmethoxy)pyridinehydrochloride

94a. 5-Amino-3-(1-methyl-2(S)-pyrrolidinylmethoxy)pyridine To a solutionof the compound of example 28a (3 g, 11.1 mmol) in methanol (125 mL) wasadded CuBr (1.38 g). The resultant mixture was allowed to stir withammonia at 130° C. for 24 hours. The excess ammonia was evaporated,methanol was removed, and the resultant residue was dissolved in water.The aqueous solution was then extracted with chloroform (3×50 mL). Thecombined organic layers were dried over anhydrous MgSO₄ and filtered.The mixture was concentrated in vacuo and the residue was purified onsilica gel to give 2.0 g (86%) of the title compound. MS (DCI/NH₃) m/e:208 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) d 7.77 (d, 1H, J=3.0 Hz)), 7.72(d,1H, J=3.0 Hz), 6.54 (t, 1H, J=3.0 Hz), 4.00-3.85 (m, 2H), 3.62-3.69 (m,1H), 3.07-3.14(m, 1H), 2.58-2.70 (m, 1H), 2.47 (s, 3H), 2.24-235 (m,1H), 1.95-2.09 (m, 1H), 1.54-1.90 (m, 2H).

94b. 5-Amino-3-(1-methyl-2(S)-pyrrolidinylmethoxy)pyridine hydrochloride

The compound from step 94a was treated with HCl in ether, then againwith HCl in dioxane, and the precipitate was collected. The salt wastriturated with ether and dried under vacuum to give the title compound.MS (DCI/NH₃) m/e: 208 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) d 7.77-7.80 (m,2H), 7.09 (t, 1H, J=2.4Hz), 4.50 (dd, 1H, J=3.4, 11 Hz), 4.34 (dd, 1H,J=5.8, 11 Hz), 3.87-4.00(m, 1H), 3.69-3.83 (m, 1H), 3.18-3.34 (m, 1H),3.03 (s, 3H), 2.31-2.46 (m, 1H), 2.00-2.30 (m, 1H). Anal. calcd for C₁₁H₁₇ N₃ O•1.6 HCl•1.0 H₂ O: C, 46.58 H, 7.32 N, 14.82. Found: C, 46.84;H; 7.46 N, 14.42.

EXAMPLE 953-((1-methyl-2-(S)-pyrrolidinyl-methoxy)-5-methylamino-pyridinetrihydrochloride

The 3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)-5amino-pyridine fromExample 94 is reacted with HCOOH and HCHO according to the method ofExample 16a. The product is purified by chromatography on silica gel andconverted into the title compound by treatment with HCl in etheraccording to Example 14c.

EXAMPLE 963-((1-methyl-2-(S)-pyrrolidinyl)methoxy)-5-methylamino-pyridinetrihydrochloride

The 3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)-5-amino-pyridine fromExample 94 is dissolved in THF and reacted with ethyl iodide accordingto standard procedures. The product is purified by chromatography onsilica gel and converted into the title compound by treatment with HClin ether according to Example 14c.

EXAMPLE 973-((1-methyl-2-(S)-pyrrolidinyl)methoxy)-5-acetylamino-pyridinedihydrochloride

The 3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)-5-amino-pyridine fromExample 94 is dissolved in THF and reacted with acetyl chlorideaccording to standard procedures. The product is purified bychromatography on silica gel and converted into the title compound bytreatment with HCl in ether according to Example 14c.

EXAMPLE 98 3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)-5-methoxy-pyridinedihydrochloride

98a. 3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)-5-bromo-pyridine-N-oxide

A sample of 3,5-dibromopyridine-N-oxide (prepared according to themethod of Y. Tamura et al., Heterocycles, 15:871-874 (1981)) is reactedwith (S)-(-)-1-methyl-2-pyrrolidinemethanol according to the procedureof Example 3a, and the product is purified by chromatography on silicagel.

98b. 3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)-5-methoxy-pyridine-N-oxide

A sample of the compound from step 98a above is reacted with sodiummethoxide in methanol according to standard procedures. The reaction isquenched with water, the product is extracted, then purified bychromatography on silica gel.

98c. 3-((1-methyl-2-(S)-pyrrolidinyl)methoxy-5-methoxy-pyridinedihydrochloride

A sample of the compound from step 98b above is reacted with hydrogen inthe presence of Raney nickel according to the method of Y. Tamura etal., Heterocycles, 15:871-874-1981). The product is purified bychromatography on silica gel and converted into the title compound bytreatment with HCl in ether according to Example 14c.

EXAMPLE 99 3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)-5-cyano-pyridinedihydrochloride

99a 3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)-5-cyan-pyridine-N-oxide

A sample of3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)-5bromo-pyridine-N-oxide, fromExample 98a above, is reacted with sodium cyanide in DMF and wateraccording to standard procedures. The solvents are removed, and theproduct is extracted, then purified by chromatography on silica gel.

99b. 3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)-5-cyano-pyridinedihydrochloride

A sample of the compound from step 99a above is reacted with hydrogen inthe presence of Raney nickel according to the method of Y. Tamura etal., Heterocycles, 15:871-874 (1981). The product is purified bychromatography on silica gel and converted into the title compound bytreatment with HCl in ether according to Example 14c.

EXAMPLE 100 3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine-5carboxylic acid methyl ester dihydrochloride

5-bromo-3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine from Example28a (272 mg, 1 mmol) in methanol (20 mL) was stirred in the presence oftrietylamine (219 mg) and palladium triphenylphosphine dichloride underan atmosphere of CO (100 psi) at 100° C. for 68 hours. The catalyst wasremoved by filtration, and the filtrate was concentrated. The residuewas purified by chromatography on silica gel to afford 42 mg of the freebase. MS (DCI/NH₃): 251 (M+H+). The free base was converted into thetitle compound by treatment with HCl in ether according to Example 14c.

EXAMPLE 1013-((1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine-5-carboxylic aciddihydrochloride

A sample of the compound from Example 100 above is hydrolyzed with 1NNaOH according to standard methods. The product is purified bychromatography on silica gel and converted into the title compound bytreatment with HCl in ether according to Example 14c.

EXAMPLE 102 3-(2-(2-(S)-pyrrolidinyl)ethoxy)pyridine dihydrochloride

102a. 1-BOC-2-(S)-pyrrolidineethanol

To a solution of 1-BOC-2-(S)-pyrrolidineethanal (6.80 g, 26.5 mmol) inanhydrous toluene (100 mL), cooled to -78° C. was added a 1M solution ofdiisobutylaluminum hydride in toluene (132.5 mL, 132.5 mmol). Thereaction was stirred at -78° C. for 2 hours, and diisobutylaluminumhydride solution (26.50 mL, 26.5 mmol) was added. The mixture wasstirred for 2 hours, then the reaction was quenched at -78° C. withmethanol (150 mL). The mixture was poured into 1M Rochelle salt (500mL), and the emulsified solution was extracted with ethyl acetate (200mL). The organic layer was washed with brine, dried over MgSO₄, andconcentrated. The residue was purified on silica gel, eluting withmethanol/methylene chloride (5:95) to yield a colorless oil (3.82 g,67%). MS (DCI/NM) m/e: 216 (M+H)⁺. ¹ HNMR (CDCl₃, 300 MHz) δ: 1.47 (s,9H), 1.58-1.76 (m, 2H), 1.82-2.05 (m, 3H), 3.31 (t, J=6.0 Hz, 2H),3.50-3.69 (m, 2H), 4.10-4.21 (m, 1H), 4.43 (dd, J=4.0, 7.0 Hz, 1H).

102b. 3-(2-(l-BOC-2-(S)-pyrrolidinyl)ethoxy)pyridine

To a solution of triphenylphosphine (3.39 g, 12.9 mmol) in THF (10 mL)was added DEAD (2.03 mL, 15.5 mmol), and the mixture was stirred at roomtemperature for 20 minutes. Then 3-hydroxypyridine (1.23 g, 15.5 mmol)in 10 mL of THF was added, and the reaction was stirred at roomtemperature for 10 minutes. The alcohol from step 102a above (2.31 g,10.80 mmol) in 10 mL of THF was then added, and the mixture was stirredfor 16 hours and concentrated in vacuo. The residue was triturated withhexane, then the filtrate was concentrated and purified on silica gel,eluting with ethyl acetate/hexane (1:1) to afford an oil (2.58 g, 84%).MS(DCI/NH₃) m/e: 293 (M+H)⁺. 1H NMR (CDCl₃, 300 MHz) δ: 1.49 (s, 9H),1.74-2.06 (m, 5H), 2.13-2.31 (m, 1H), 3.37-3.40 (m, 2H), 3.95-4.12 (m,3H), 7.18-7.21 (m, 1H), 8.21 (d, J=8.0 Hz, 1H), 8.29-8.31 (m, 1H).

102c. 3-(2-(2-(S)-pyrrolidinyl)ethoxy)pyridine dihydrochloride

To a solution of the compound from step 102b above (60 mg, 0.20 mmol) in3 mL of ethanol at Q20 C was added saturated HCl in ethanol (10 mL), andthe reaction mixture was stirred for 30 minutes at 0° C. The volatileswere removed under vacuum, and the residue was purified on a column ofsilica gel, eluting with methanol/methylene chloride (5:95). The productwas treated with a saturated solution of HCl/EtOH and held under vacuumfor 24 hours to afford a white solid. MS (DCI/NH₃) m/e: 193 (M+H)⁺, 210(M+NH₄)⁺. ¹ H NMR (D₂ O, 300 MHz) δ: 1.69-1.86 (m, 1H), 1.91-2.20 (m,3H), 2.26-2.43 (m, 2H), 3.28-3.47 (m, 2H), 3.70-3.85 (m, 1H), 4.27-4.45(m, 2H), 7.82 (dd, J_8.5, 5.0 Hz, 1H), 7.98 (dd, J=9.0, 4.0 Hz, 1H),8.35 (d, J=6.0 Hz, 1H), 8.45 (d, J=2.0 Hz, 1H). Anal. Calc. for C₁₁ H₁₆N₂ O•2.3 HCl: C, 47.84; H, 6.68; N, 10.14; Found C, 47.48; H. 6.92; N,9.94. α!²⁵ _(D) =+41.62° (c=0.41, methanol).

EXAMPLE 103 3-(2-(1-methyl-2-(S)-pyrrolidinyl)ethoxy)pyridinedihydrochloride

A 400 mg sample of 3-(2-(2-(S)-pyrrolidinyl)ethoxy)pyridinedihydrochloride, from Example 102 above, was dissolved in 14 mL of 37%HCHO, 14 mL of HCOOH was added, and the reaction mixture was stirred atreflux for 2.5 hours. The solution was washed with ether, adjusted tobasic pH with K₂ CO₃ and extracted with methylene chloride. The extractwas dried over MgSO₄ and concentrated. The residue was purified on acolumn of silica gel, eluting with 10% methanol in methylene chloride.The compound was converted to the salt by the HCl in ether according toExample 14c to afford the title compound. MS (DCI/NH₃) m/e: 207 (M+H)⁺.¹ H NMR (D₂ O, 300 MHz) δ: 1.71-1.98 (m, 1H), 2.00-2.23 (m, 3H),2.37-2.45 (m, 1H), 2.50-2.63 (m, 1H), 2.98 (s, 3H), 3.13-3.25 (m, 1H),3.53-3.67 (m, 1H), 3.68-3.78 (m, 1H), 4.31-4.48 (m, 2H), 8.00 (dd,J=11.0, 7.0 Hz, 1H), 8.20 (dd, J=10.5, 5.0 Hz, 1H), 8.42 (d, J=6.5 Hz,1H), 8.50 (d, J=5.0 Hz, 1H). Anal. Calc. for C₁₂ H₁₈ N₂ OF•1.9 HCl•1.1H₂ O: C, 48.49; H, 7.46; N, 9,42; Found C, 48.51; H, 7.69; N, 9.61. α!²⁵_(D) =+36.2820 (C=0.5, H₂ O).

EXAMPLE 104 3-(2-(2-(S)-pyrrolidinyl)ethoxy)-6-chloropyridinedihydrochloride

104a 3-(2-(1-IBOC-2-(S)-pyrrolidinyl)ethoxy-6-chloropyridine

To a solution of triphenylphosphine (5.90 mmol, 1.54 g) in THF (17 mL)was added DEAD (5.90 mmol, 1.03 g) and the mixture was stirred at roomtemperature for 10 minutes. To the mixture was added a solution of2-chloro-5-hydroxypyridine (5.90 mmmol, 0.7611 g) in THF (5.0 mL) andstirring was continued for 10 minutes. The alcohol (1.06 g, 4.90 mmol)from Example 102a in THF (10 mL) was added and the mixture was stirredat room temperature for 16 hours. The mixture was concentrated in vacuo,triturated with hexane, filtered and the volatiles removed. The residuewas purified on silica gel, eluting with ethyl acetate/hexane (1:1)which afforded 1.57 g (98%) of a yellow oil. MS(DC;/NH₃) 327 (M+H)⁺, 344(M+NH₄)⁺. 1H NMR(CDCl₃, 300MHz): 1.18-1.80 (m, 2H), 1.45 (s, 9H),1.71-2.03 (m, 5H), 2.13-2.28 (bs, 1l), 3.28-3.46 (m, 1H), 3.96-4.10 (m,2H), 7.14-7.25 (m, 2H), 8.01-8.07 (m, 1H).

104b. 3-(2-(2-(S)-pyrrolidinyl)ethoxy)-6-chloropyridine dihydrochloride

To a solution of 124 mg (0.40 mmol) of the compound from step 104a abovein 3 mL of ethanol was added 10 mL of satd HCl in ethanol, and thereaction mixture was stirred for 1 hour at room temperature. Thevolatiles were removed under vacuum, and the residue was acidified andextracted with methylene chloride. The aqueous solution was made basicand extracted with methylene chloride. The extract was dried over MgSO₄and concentrated. The residue was purified on a column of silica gel,eluting with 10% methanol in methylene chloride. The compound wasconverted to the salt by the HCl in ether according to Example 14c toafford the tire compound. MS (DCI/NH₃) m/e: 227 (M+H)⁺. ¹ H NMR (D₂ O,300 MHz) δ: 1.69-1.85 (m, 1H), 1.91-2.18 (m, 2H), 2.21-2.37 (m, 3H),3.23-3.43 (m, 2H), 3.67-3.81 (m, 1H), 4.15-4.46 (m, 2H), 7.47 (m, 2H),8.06 (d, J=3.5 Hz, 1).. Anal. Calc. for C₁₁ H₁₅ N₂ OCl•2 HCl: C, 45.09;H, 5.71; N, 9.34; Found C, 45.04; H, 6.01; N, 9.05. α!²⁵ D=+19.00°(c=0.15, H₂ O).

EXAMPLE 105 3-(2-(1-methyl-2-(S)-pyrrolidinyl)ethoxy-6-chloropyridinedihydrochloride

A 565 mg sample of 3-(2-(2-(S)-pyrrolidinyl)ethoxy)6-chloropyridinedihydrochloride, from Example 104 above, was dissolved in 27 mL of 37%HCHO, 27 mL of HCOOH was added, and the reaction mixture was stirred atreflux for 30 minutes. The solution was washed with ether, adjusted tobasic pH with K₂ CO₃ and extracted with methylene chloride andchloroform. The extract was dried over MgSO₄ and concentrated. Theresidue was purified on a column of silica gel, eluting with 10%methanol in methylene chloride. The compound was converted to the saltby the HCl in ether-according to Example 14c to afford the titlecompound. MS (DCI/NH₃) m/e: 241 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ:1.82-1.97 (m, 1H),. 2.01-2.20 (m, 3H), 2.38-2.54 (m, 2H), 2.98 (s, 3H),3.05-3.25 (m, 1H), 3.50-3.63 (, 1H), 3.65-3.77 (m, 1H), 4.13-4.32 (m,2H), 7.40 (d, J=10 Hz, 1H), 7.48 (dd, J=10.5, 4.0 Hz, 1H), 8.10 (d,J=3.0 Hz, 1H). Anal. Calc. for C₁₂ H₁₇ N₂ OCl•1.9 HCl: C, 46.49; H,6.14; N, 9.03; Found C, 46.70; H, 6.06; N, 9.04. α!²⁵ _(D) =+21.00°(c=0.20, H₂ O).

EXAMPLE 106 3-(2-(S)-pyrrolidinylmethylthioxy)pyridine dihydrochloride

106a. 3-(1-BOC-2-(S)-pyrrolidinylmethylthioxy)pyridine

To a solution of triphenylphosphine (1.8 mmol, 0.472 g) in THF (8 mL)was added DEAD (1.8 mmol, 0.283 mL) and the mixture was stirred at )° C.for 20 minutes. To this mixture was added 166.5 mg (1.5 mmol) sample of3-thiopyridine (prepared from 3-pyridinesulfonic acid according to theprocedure of A. Albert and G. B. Barlin, J. Chem. Soc., 1959, 2384) and361.8 mg (1.8 mmol) of (S)-1-BOC-2-pyrrolidinemethanol (from Example 15aabove). The reaction mixture was warmed to room temperature and stirredfor 16 hours. The mixture was concentrated in vacuo. The residue waspurified on silica gel to five 440 mg of the title compound. MS(DCI/NH₃) m/e: 295 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ: 8.65-8.58 (m,1H), 8.46-8.36 (m, 1H), 7.88-7.69 (m, 1H), 4.06-3.88 (m, 1H), 3.65-32.8(m, 4H), 2.18-1.74 (m, 4H), 1.44 (s, 9H).

106b. 3-(2-(S)-pyrrolidinylmethylthioxy)pyridine dihydrochloride

The compound from step 106a was treated with HCl in ether, then againwith HCl in dioxane, and the precipitate was collected. The salt wastriturated with ether and dried under vacuum to give the title compound.MS (DCI/NH₃) m/e: 195 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ: 8.91-8.84 (m,1H), 8.64-8.57 (m, 1H), 8.48-8.40 (m, 1H), 7.88-7.82 (m, 1H), 3.86-3.72(m, 1H), 3.66&3.57 (m, 1H), 3.44-3.28 (m, 3H), 2.36-2.23 (m, 1H),2.18-1.97 (m, 2H), 1.88-1.76 (m, 1H).

EXAMPLE 107 3-(1-methyl2-(S)-pyrrolidinylmethylthioxy)pyridinedihydrochloride

A 120 mg sample of 3-(2-(S)-pyrrolidinylmethylthioxy)pyridinedihydrochloride, from Example 106 above, was dissolved in 2 mL of 37%HCHO, 1 mL of HCOOH was added, and the reaction mixture was stirred atreflux for 30 minutes. The solution was washed with ether, adjusted tobasic pH with K₂ CO₃ and extracted with methylene chloride andchloroform. The extract was dried over MgSO₄ and concentrated. Theresidue was purified on a column of silica gel, eluting with 10%methanol in methylene chloride. The compound was converted to the saltby the HCl in ether according-to Example 14c to afford 84.5 mg of thetitle compound. MS (DCI/NH₃) m/e: 209 (M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) δ:8.69-8.65 (m, 1H), 8.53-8.48 (m, 1H), 8.13-8.09 (m, 1H), 7.60-7.54 (m,1H), 3.77-3.68 (m, 1H), 3.61-3.48 (m, 2H), 3.42-3.34 (m, 1H), 3.22-3.12(m, 1H), 2.93 (s, 3H), 2.46-2.33 (m, 1H), 2.18-1.97 (m, 2H), 1.94-1.80(m, 1H).

EXAMPLE 108 5-Nitro-3-(1-methyl-2(S)-pyrrolidinylmethoxy)pyridinehydrochloride

108a. 3.5-Dinitro-2-pyridinylhydrazine

Hydrazine (anhydrous, 0.75 ml, 23.9 mmol) was added to a solution of2-chloro-3,5-dinitro-pyridine (3.42 g, 16.8 mmol) in methanol (25 mL).The resultant mixture was stirred at room temperature overnight. Solventwas evaporated, and the residue was washed with water and methanolseveral times to remove the impurities. A dark solid powder was obtained(3.0 g). MS (DCI/NH₃) m/e: 200 (M+1). 1H NMR(DMSO-d₆, 300MHz) δ: 9.25(m, 1H), 9.06 (m, 1H).

108b. 3.5-dinitro-pyridine

Silver acetate (2.0 g) was added to a solution of the crude3,5-dinitro-pyridinyl-hydrazine (2.2 g) in a mixture of methanol:H₂ O(1:1,6 ml), and the mixture was stirred at reflux overnight. Solvent wasevaporated, then water and conc. NH₄ OH were added. The mixture wasextracted with ethyl ether, the combined extracts were dried over MgSO₄,concentrated and purified by column chromatography (5:1 hexane: ethylacetate) to give the title compound (400 mg) in 21.8% yield. MS(DCI/NH₃) m/e: 124 (M-46+1). ¹ H NMR (CDCl₃, 300MHz) δ: 9.77 (m, 2H),9.27 (m, 1H).

108c. 5Nitro-3-(1-methyl-2(S)-pyrrolidinylmethoxy)pyridine

1-Methylpyrrolidinylmethanol (0.46 ml, 3.9 mmol) was added to asuspension of NaH in DMF at room temperature. After stirring at roomtemperature for 30 minutes, 3,5-dinitro-pyridine (0.34 g, 4 mmol) wasadded, and the mixture was allowed to stir at room temperature for 16hours. The mixture was diluted with 1:1 water/brine, and the aqueoussolution was extracted with ether. The combined ether layers were driedover MgSO₄, filtered and concentrated. The residue was chromatographed,eluting with CH₂ Cl₂ : methanol (10:0.5) to afford 70 mg of the titlecompound. MS (DCI/NH₃) m/e: 238 (M+1). ¹ H NMR (CDCl₃, 300MHz) δ: 9.06(m, 1H), 8.62 (d, 1H), 7.97 (m, 1H), 4.07 (m, 2H), 3.50 (s, 3H), 3.13(m, 1H), 2.73 (m, 1H), 2.35 (m, 1H), 2.05 (m, 1H), 1.82 (m, 3H).

108d. 5Nitro-3-(-methyl-2(S)-pyrrolidinylmethoxy)pyridine hydrochloride

The compound from step 108c was treated with HCl in ether (and a fewdrops of methanol). The precipitate was collected. The salt wastriturated with ether and dried under vacuum to give the title compound.MS (DCI/NH₃) m/e: 238 (M+1). ¹ H NMR (CD₃ OH, 300MHz) δ: 9.09 (s, 1H),8.76 (m, 1H), 8.29 (m, 1H), 4.64 (dd, J=3.4, 1l.2Hz,1H), 4.50 (dd,J=6.5, 11.2Hz, 1H), 3.97 (m, 1H), 3.78 (m, 1H), 3.26 (m, 1H), 3.10 (s,3H), 2.44 (m, 1H), 2.29-2.06 (m, 3H). Anal. Calc. for C₁₁ H₁₅ N₃ O₃•1.2HCl•0.5 Methanol: C, 46.50; H, 6.18; N, 14.15. Found: C, 46.52; H,6.01; N, 13.93.

EXAMPLE 109 109b. 5,6-Dichloro-3-(2-(S)-azetidinylmethoxy)pyridinehydrochloride

109a. 5,6-Dichloro-3-hydroxypyridine

The title compound was prepared following the procedures described byKoch and Schnatterer, Synthesis, 499,1990, and Doyle and Bryker, J. Org.Chem., 44,1572, 1979.

109b.5,6-Dichloro-3-(1-t-butyloxycarbonyl-2-(S)-azetidinylmethoxy)pyridine

N-Boc-2-(S)-azetidinol from Example 7b (1.55 g, 8.28 mmol),triphenylphosphine (2.6 g, 9.94 mmol), DEAD (1.6 mL, 9.94 mmol), and5,6-dichloro-3-hydroxypyridine (1.5 g, 9.10 mmol) were allowed to reactas in Example 9. The crude product was chromatographed eluting withEtOAc:hexane (1:5) to give 1.08 g of a waxy solid, 39% yield. MS (CI)m/e 333 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) d 7.97 (d, J=2.8 Hz, 1H), 7.41(d, J=2.8 Hz, 1H), 4.56-4.48 (m, 1H), 4.40-4.30 (m, 1H), 4.12 (dd,J=10.1, 2.7 Hz, 1H-), 3.95-3.82 (m, 2H), 2.42-2.22 (m, 2H), 1.42 (s,9H).

109c. 5.6-Dichloro-3-(2-(S)-azetidinylmethoxy)pyridine

The compound of step 109b was dissolved in CH₂ Cl₂ (10 mL) and TFA (10mL) was added at 0° C. After 30 minutes of stirring the reaction waswarmed to room temperature and stirred for an additional 45 minutes.Solvent was removed, and the residue was partitioned between sat'd K₂CO₃ solution and CH₂ Cl₂. The aqueous layer was further extracted withCH₂ Ca₂ (4X), and the combined organic extracts wer dried over MgSO₄ andconcentrated. The crude material was chromatographed eltuing with 10%methanol/CHCl₃ followed by 10% methanol/CHCl₃ /0.5% NH₄ OH to give 475mgs of a pale solid, 64% yield. m.p. =59-60° C. MS (CI) m/e 233 (M+H)⁺.¹ H NMR (CDCl3, 300 MHz) δ: 8.01 (d, J=2.8 Hz, 1H), 7.37 (d, J=2.8 Hz,1H), 4.33-4.24 (m, 1H), 4.08-3.98 (m, 2H), 3.73 (dd, J=15.8, 8.4 Hz,1H), 3.49-3.41 (m, 1H), 2.44-2.21 (m, 2H).

109d. 5.6-Dichloro-3-(2-(S)-azetidinylmethoxy)pyridine hydrochloride

The compound from step 109c (338 mg, 1.45 mmol) was slurried in ether(15 mL), and ether saturated with HCl gas was added. Solvent was removedand the remaining white solid was recrystallized from methanol/Et₂ O togive 317 mg of short white needles, 81% yield. m.p. =181-182° C. MS (CI)m/e 233 (M+H)⁺. ¹ H NMR (20, 300 MHz) δ: 8.13 (d, J=2.9 Hz, 1H), 7.79(d, J=2.9 Hz, 1H), 4.99-4.91 (m, 1H), 4.44 (d, J=4.4 Hz, 2H), 4.21-4.03(m, 2H), 2.74-2.65 (m, 2H). Anal. calc. for C₉ H₁₁ Cl₃ N₂ O: C, 40.10;H, 4.11; N, 10.39; Found: C, 39.89; H, 4.08; N, 10.25.

EXAMPLE 110 5,6-Dichloro-3-(1-methyl-2-(S)-azetidinylmethoxy)pyridinehydrochloride

110a 5,6-Dichloro-3-(1-methyl-2-(S)-azetidinylmethyloxy)pyridine

The compound of Example 109c (126 mg, 0.54 mmol) was slurried in water(4 mL) and acetic acid added (3 mL) until the solution becamehomogeneous. An excess of formalin was added, followed by carefuladdition of sodium cyanoborohydride until the starting material wasconsumed. A small amount of 12 M HCl was added and the solution waswashed with ether. The aqueous phase was then basified with solid K₂ CO₃and 15% NaOH soln and then extracted with CH₂ Cl₂ (X3). The organiclayers were combined, dried over MgSO₄, concentrated, and purified byflash chromatography using 5% methanol/CHCl₃ as the eluant to give 105mg of a clear oil, 79% yield. MS (CI) m/e 247 (M+H)⁺. ¹ H NMR (CDCl₃,300 MHz) d: 8.01 (d, J=2.7 Hz, 1H), 7.36 (d, J=2.7 Hz, 1H), 4.00 (d,J=4.8 Hz, 2H), 3.49-3.33 (m, 2H), 2.92-2.83 (m, 1H), 2.39 (s, 3H),2.12-2.04 (m, 2H).

110b. 5,6Dichloro-3-(1-methyl-2-(S)-azetidinylmethoxy)pyridinehydrochloride

The compound from step 110a (99.0 mg, 0.40 mmol) was dissolved in ether(5 mL) and ether saturated with HCl gas was added. Solvent was removedand the remaining white solid was recrystallized from methanol/ether togive 75 mg of a white powder, 66% yield. m.p. 144-145 C. MS (CI) m/e 247(M+H)⁺. ¹ H NMR (D₂ O, 300 MHz) d: 8.13 (d, J=2.7 Hz, 1H), 7.78 (d,J=2.7 Hz, 1H), 4.88-4.75(m, 1H partially buried under solvent),4.53-4.43 (m, 2H), 4.30-4.22 (m, 1H), 4.08-3.97 (m, 1H), 2.99 (s, 3H),2.75-2.57 (m, 2H). Anal. calc. for C₁₀ H₁₃ Cl₃ N₂ O•0.1 HCl: C, 42.09;H, 4.66; N, 9.82; Found: C, 41.86; H, 4.57; N, 9.62.

What is claimed is:
 1. A compound having the formula: ##STR13## or apharmaceutically acceptable salt thereof wherein indicates a chiralcenter; X is selected from O or S, wherein, for X equal to S,n is 1, 2,or 3: R¹ is H, allyl, or C₁ -C₆ -alkyl; R² is a hydrogen or a singlechiral or achiral substituent, and when substituted at the 3-position isa C₁ -C₃ -alkyl group; or when substituted at the 4-position is selectedfrom the group consisting of CH₂ OH, CH₂ F, CH₂ -O-methyl, Br, Cl, F,OH, CN, C₁ -C₃ -alkoxyl, O-CO-CH₃ and O-methane-sulfonyl; or whensubstituted at the 5-position is a C₁ -C₃ alkyl group; A is selectedfrom the group consisting of ##STR14## wherein R³ is H or C₁ -C₆ -alkyl;and D is selected from the group consisting of ##STR15## wherein y=1,2,or 3; and R⁴ is H or, when substituted at the 2-position, isadditionally selected from the group consisting of hydroxy, C₁ -C₃-alkyl, C₁ -C₃ -alkoxy, F, and Cl; and when substituted at the 4-, 5-,or 6-position is additionally selected from the group consisting of (a)hydroxyl, CF₃, C₁ -C₃ alkoxy, nitro, amino, N(C₁ -C₃ alkyl)-CO(C₁ -C₃alkyl), C₁ -C₃ alkylamino, di-(C₁ -C₃ alkyl)amino cyano, COOH, COO-(C₁-C₃ alkyl), CONH₂, CONH-(C₁ -C₃ alkyl), CO-N(C₁ -C₃ alkyl)₂, andCO-NH(benzyl); (b) halogen or C₁ -C₃ alkyl,with the provisos that when yis 1 or 2, then one R⁴ group must be substituted at the 4-, 5-, or6-position and be selected from the group (a) above, and when y is 3then at least two of the substituents must be selected from group (b)above; ##STR16## and with the proviso that when A is ##STR17## thechiral center must be (S); or for X equal to O in a compound of formulaI, ##STR18## A is selected from wherein n is 1-3; R¹ , R², R³ , D and(R⁴)y are as above with the proviso that the chiral center must be (S);or in a compound of formula I with X═O, A is selected from --CHR³ --,wherein n is 1-3; R¹ is allyl; R², R³, D and (R⁴)_(y) are as above; or nis 1 or 3; R¹ is H or C₁ -C₆ alkyl; R² is selected from a single chiralor achiral substituent and, when substituted at the 3-position is aC1-C3 alkyl group; or, when substituted at the 4-position is selectedfrom CH₂ OH, CH₂ F, CH₂ O-methyl, Br, Cl, F, OH, CN, C1-C3alkoxyl,O-CO-CH₃ and O-methanesulfonyl; or when substituted at the 5-position isa C₁ -C₃ alkyl group; R³, D and (R⁴)y are as defined above; or n is 2;R¹ is H or C₁ -C₆ alkyl; R² is selected from a single chiral or achiralsubstituent and, when substituted at the 3-position is a C₁ -C₃ alkylgroup; or, when substituted at the 4-position is selected from CH₂ F,CN, O-CO-CH₃ and O-methanesulfonyl; or when substituted at the5-position is a C₁ -C₃ alkyl group; R³, D and (R⁴)_(y) are as definedabove with the proviso that the compound3-(1-methyl-5-methyl-2-(S)-pyrrolidinylmethyloxy)pyridinedihydrochloride is excluded; or n is 1-3; R¹ is H or C₁ -C₆ alkyl; R² isH or, for n equal to 2, is a single substituent substituted at the4-position and selected from OH, C₁ -C₃ alkyl, OC₁ -C₃ alkyl, CH₂ OH,CH₂ OMe, Br, Cl or F; D is selected from ##STR19## wherein y is 1-3 andR⁴, when substituted at the 2-position, is selected from the groupconsisting of hydroxy, C₁ -C₃ -alkyl, C₁ -C₃ -alkoxy, F and Cl; and whensubstituted at the 4-, 5- or 6-position is selected from the groupconsisting of (a) CF₃, nitro, amino, N(C₁ -C₃ alkyl)-CO(C₁ C₃ alkyl), C₁-C₃ alkylamino, di-(C₁ -C₃ alkyl)amino cyano, COOH, COO-(C₁ -C₃ alkyl),CONH₂, CONH-(C₁ -C₃ alkyl), CO-N(C₁ -C₃ alkyl)2, and CO-NH(benzyl); (b)halogen or C₁ -C₃ alkyl,with the provisos that when y is 1 or 2, thenone R⁴ group must be substituted at the 4-, 5-, or 6-position and beselected from the group (a) above, and when y is 3 then at least two ofthe substituents must be selected from group (b) above.
 2. A compoundaccording to claim 1, wherein the chiral center is of the(S)-configuration.
 3. A compound according to claim 1, wherein thechiral center is of the (R)-configuration.
 4. A compound according toclaim 1 wherein n is 1 or 2, R¹ is H or methyl, R² is as defined inclaim 1, R³ is H and D is ##STR20## wherein R⁴ and y are as defined inclaim
 1. 5. A compound according to claim 4, wherein n is
 1. 6. Acompound according to claim 4, wherein n is 2, and R¹ and R² are H.
 7. Acompound according to claim 4, wherein n is 2, the compound is of the(S)-configuration, R¹ is methyl and R² is H.
 8. A compound according toclaim 1, selected from the group consistingof3-(1-(1-methyl-2-(S)-pyrrolidinyl)ethoxy)pyridine;3-(1-methyl-4-ethyl-2-(S)-pyrrolidinylmethoxy)-5-trifluoromethylpyridine;3-((1-methyl-2-(R)-pyrrolidinyl)methoxy)trifluoromethylpyridine;3-((cis-1-methyl-3-propyl-2-pyrrolidinyl)methoxy)pyridine;3-((cis-3-propyl-2-pyrrolidinyl)methoxy)pyridine;3-(2-(S)-pyrrolidinylmethoxy)-5-trifluoromethylpyridine;3-(2-(R)-pyrrolidinylmethoxy)-5-trifluoromethylpyridine;3-(2-(S)-azetidinylmethoxy)-5-trifluoromethylpyridine;3-((trans-4-methanesulfonyloxy-1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine3-((cis-4-cyano-1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine;3-((cis-5-n-butyl-1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine;3-((cis-4-fluoromethyl-1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine;3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)-5-nitro-pyridine;3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)-5-amino-pyridine;3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)-5-methylamino-pyridine;3-((1-methyl-2-(R)-pyrrolidinyl)methoxy)-5-methylamino-pyridine;3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)-5-acetylamino-pyridine;3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)-5-cyano-pyridine;3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine-5-carboxylic acid ethylester; 3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine-5-carboxylicacid; 3-(2-(2-(S)-pyrrolidinyl)ethoxy)pyridine;3-(2-(1-methyl-2-(S)-pyrrolidinyl)ethoxy)pyridine;3-(2-(1-methyl-2-(S)-pyrrolidinyl)ethoxy-6-chloropyridine;3-(2-(S)-pyrrolidinylmethylthioxy)-6-chloropyridine;3-(1-methyl-2-(S)-pyrrolidinylmethylthioxy)-6-chloropyridine;5-amino-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine hydrochloride;5-nitro-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine3-((trans-4-methoxy-1-methyl-2-(S)-pyrrolidinyl)methoxypyridine; and3((trans-4-methoxy-2-(S)-pyrrolidinyl)methoxy)pyridine.
 9. A compoundaccording to claim 4 selected from the group consistingof3-(1-(1-methyl-2-(S)-pyrrolidinyl)ethoxy)pyridine; 3-(1-methyl-2-(S)pyrrolidinylmethoxy)-5-trifluoromethylpyridine;3-((cis-3-propyl-2-pyrrolidinyl)methoxy)pyridine;3-(2-(S)-pyrrolidinylmethoxy)-5-trifluoromethylpyridine;3-(2-(R)-pyrrolidinylmethoxy)-5-trifluoromethylpyridine;3-(2-(S)-azetidinylmethoxy)-5-trifluoromethylpyridine;5-amino-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine hydrochloride; or5-nitro-3-(1 -methyl-2-(S)-pyrrolidinylmethoxy)pyridine hydrochloride.10. A compound according to claim 5 selected from the group consistingof3-(2-(S)-azetidinylmethoxy)-5-trifluoromethylpyridine; and or apharmaceutically acceptable salt thereof.
 11. A compound according toclaim 6 having the name3-(2-(R)-pyrrolidinylmethoxy)-5-trifluoromethylpyridine or apharmaceutically acceptable salt thereof.
 12. A compound according toclaim 7 selected from the group consistingof3-(1-methyl-2,(S)-pyrrolidinylmethoxy)-5-trifluoromethylpyridine;5-amino-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine; and5-nitro-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine or apharmaceutically acceptable salt thereof.
 13. A compound according toclaim 2 selected from the group consistingof3-(1-(1-methyl-2-(S)-pyrrolidinyl)ethoxy)pyridine;3-((cis-1,5-dimethyl-2-(S)-pyrrolidinyl)methoxy)pyridine; 3-(1-methyl-2-(S)-pyrrolidinylmethoxy)-5-trifluoromethylpyridine;3-(2-(S)-pyrrolidinylmethoxy)-5-trifluoromethylpyridine;3-(2-(S)-azetidinylmethoxy)-5-trifluoromethylpyridine;3-((trans-4-methanesulfonyloxy-1-methyl-2(S)-pyrrolidinyl)methoxy)pyridine;3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)-5-methylamino-pyridine;3-((1-methyl-2-( S!a)pyrrolidinyl)methoxy)-5-methylamino-pyridine;3-((1-methyl-2-(S)-pyrrolidinyl)methoxy-5-acetylamino-pyridine;3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)-5-cyano-pyridine;3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine-5-carboxylic acid,methyl ester;3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine-5-carboxylic acid;3-(2-(2-(S)-pyrrolidinyl)ethoxy)pyridine;3-(2-(1-methyl-2-(S)-pyrrolidinyl)ethoxy)pyridine;3-3-(2-(2-(S)-pyrrolidinyl)ethoxy-6-chloropyridine; 3-(2-(1-methyl-2-(S)-pyrrolidinyl)ethoxy-6-chloropyridine;3-(2-(S)-pyrrolidinylmethylthioxy)-6-chloropyridine; 3-(1-methyl2-(S)-pyrrolidinylmethylthioxy)-6-chloropyridine;5-amino-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine hydrochloride; or5-nitro-3-(1 -methyl-2-(S)-pyrrolidinylmethoxy)pyridine hydrochloride.14. A compound according to claim 3 selected from the group consistingof3-((1 -methyl-2-(R)-pyrrolidinyl)methoxy)-5-trifluoromethylpyridine;3-(2-(R)-pyrrolidinylmethoxy)-5-trifluoromethylpyridine; or apharmaceutically acceptable salt thereof.
 15. A pharmaceuticalcomposition comprising a pharmaceutically acceptable amount of acompound according to claim 1 and a pharmaceutically acceptable carrier.16. A method for controlling dopamine release in a mammal in need oftreatment thereof comprising administering a pharmaceutically effectiveamount a compound in accordance with claim
 1. 17. A compound of theformula: ##STR21## with n=1,2 or 3; * is a chiral center;R¹ is H or C₁-C₆ alkyl; R² is H or, for n=2, a single substituent at the 4-positionselected from the group consisting of --C₁ -C₃ alkyl, --OH, --CH₂ OH,--CH₂ O-methyl, Br, Cl or F; R³ is H or C₁ -C₆ alkyl; and D is selectedfrom: ##STR22## wherein y=1 and R⁴ is substituted at the 4-, 5-, or6-position with --OH or C₁ -C₃ alkyloxy or a pharmaceutically acceptablesalt thereof.
 18. A compound according to claim 17 selected from thegroup consisting of:2-((1-methyl-2-(S)-pyrrolidinyl)methoxy)pyrazine;2-((1-methyl-2-(R)-pyrrolidinyl)methoxy)-6-chloropyridazine;2-(2-(S)-azetidinylmethoxy)pyrazine;2-((1-methyl-2-(S)-azetidinyl)methoxy)pyrazine;2-((1-methyl-2-(S)-pyrrolidinyl)methoxy)thiazole;3-((1-methyl-2-(S)-pyrrolidinyl) methoxy)-6-chloropyridazine;6-chloro-3-((1-methyl-2-(S)-azetidinyl)methoxypyridazine;3-((trans-1-methyl-4-hydroxy-2(S)-pyrrolidinyl)methoxy)pyridine;3-((trans-1,4-dimethyl-2-(S)-pyrrolidinyl)methoxy)pyridine;3-((trans-4-methoxy-1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine orpyrrolidinyl)methoxy)pyridine; or pharmaceutically acceptable saltthereof.
 19. A compound according to claim 17 selected from the groupconsistingof3-((cis-4-hydroxymethyl-1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine;3-((4-methoxymethyl-1-methyl-2-(S)pyrrolidinyl)methoxy)pyridine;3-((trans-4-hydroxy-2-(S)-pyrrolidinyl)methoxy)pyridine;3-((cis-4-flouro-1-methyl-2-(S)-pyrrolidinylmethoxy)pyridine;3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridazine;3-((trans-4-hydroxymethyl-1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine;5-(1-methyl-2-(S)pyrrolidinylmethoxy)pyrimidine;3-(2-(S)-azetidinylmethoxy)-6-chloropyridazine;3-(2-(R)pyrrolidinylmethoxy)quinoline; or a pharmaceutically acceptablesalt thereof.
 20. A compound according to claim 17 wherein n is 1 or 2,R¹ is H or methyl, R² is as defined above, R³ is H, and B is as definedabove selected from the group consistingof:2-(2-(S)-azetidinylmethoxy)pyrazine;2-((1-methyl-2-(S)-azetidinyl)methoxy)pyrazine;3-((trans-1,4-dimethyl-2(S)-pyrrolidinyl)methoxy)pyridine or3-((trans-1-methyl-4-ethyl-2(S)-pyrrolidinyl)methoxy)pyridine or apharmaceutically acceptable salt thereof.
 21. A compound according toclaim 17 wherein n is 1 selected from the group consistingof:2-((S-methyl-(S)-azetidinyl)pyrazine;2-((1-methyl-2-(S)-azetidinyl)methoxy)pyrazine or6-chloro-3-((1-methyl-2(S)-azetidinyl)methoxy)pyridazine or apharmaceutically acceptable salt thereof.
 22. A compound according toclaim 17 wherein the chiral center is of the (S) configuration and isselected from the group consistingof:2-((1-methyl-2-(S)-pyrrolidinyl)methoxy)pyrazine;2-(2-(S)-azetidinylmethoxypyrazine;2-((1-methyl-2-(S)-azetidinyl)methoxy)pyrazine;2-((1-methyl-2-(S)-pyrrolidinyl)methoxy)pyrazine;2-((1-methyl-2-(S)pyrrolidinyl)methoxy)thiazole;3-((1-methyl-2-(S)pyrrolidinyl)methoxy)-6-chloropyridazine;6-chloro-3-((1-methyl-2-(S)-azetidinyl)methoxy)pyridazine;3-((trans-1-methyl-4-hydroxy-2(S)-pyrrolidinyl)methoxy)pyridine;3-((trans-1,4-dimethyl-2-(S)-pyrrolidinyl)methoxy)pyridine or3-((trans-1-methyl-4-ethyl-2-(S)-pyrrolidinyl)methoxy)pyridine or apharmaceutically acceptable salt thereof.
 23. A compound according toclaim 17 wherein the chiral center is (R) and is selected from the groupconsistingof:2-((1-methyl-2-(R)-pyrrolidinyl)methoxy)-6-chloropyridazine or apharmaceutically acceptable salt thereof.
 24. A compound according toclaim 17 selected from the group consistingof:3-(1-methyl-2-(S)-pyrrolidinylmethoxy)quinoline or4-(1-methyl-2-(S)-pyrrolidinylmethoxy)isoquinoline or a pharmaceuticallyacceptable salt thereof.
 25. A compound which is selected from:3-((1,5-dimethyl-2-(S)-pyrrolidinyl)methoxy)pyridine.
 26. A compound which isselectedfrom:3-((trans-4-cyanomethyl-1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridineor 6-hydroxymethyl-3-((1-methyl-2-(S)-pyrrolidinyl)methoxy)pyridine. 27.A pharmaceutical composition comprising a pharmaceutically acceptableamount of a compound according to claim 17 and a pharmaceuticallyacceptable carrier.
 28. A method for controlling dopamine release in amammal in need of treatment thereof comprising administering apharmaceutically effective amount of a compound according to claim 17.29. A method of activating a cholinergic channel comprisingadministering a pharmaceutically effective amount of a compound ofclaim
 1. 30. A method of activating a cholinergic channel comprisingadministering a pharmaceutically effective amount of a compound of claim17.
 31. A compound of the formula: ##STR23## wherein n is 2; * is achiral center;R¹ is H or C₁ -C₆ alkyl; R² is a single substituent at the4-position selected from the group consisting of --C₁ -C₃ alkyl, --OH,--CH₂ OH, --CH₂ O-methyl, Br, Cl or F; R³ is H or C₁ -C₆ alkyl; and D isselected from: ##STR24## wherein y=1 and R⁴ is H or a pharmaceuticallyacceptable salt thereof.